AU2021271806A1 - Compositions and methods for increasing efficacy of a drug - Google Patents

Compositions and methods for increasing efficacy of a drug Download PDF

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AU2021271806A1
AU2021271806A1 AU2021271806A AU2021271806A AU2021271806A1 AU 2021271806 A1 AU2021271806 A1 AU 2021271806A1 AU 2021271806 A AU2021271806 A AU 2021271806A AU 2021271806 A AU2021271806 A AU 2021271806A AU 2021271806 A1 AU2021271806 A1 AU 2021271806A1
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virus
inhibitor
cathepsin
drug
peptidyl
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AU2021271806A
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Sina Bavari
Simon NEWMAN
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Healion Bio Inc
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Healion Bio Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Abstract

The present disclosure relates to a composition and method for enhancing a drug's efficacy by combining the drug with a mammalian protease inhibitor such as a cathepsin inhibitor. Methods for using the combination of the disclosure for treatment of disease are described.

Description

COMPOSITIONS AND METHODS FOR INCREASING EFFICACY OF A DRUG
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States provisional patent application number 63/025,770 filed on May 15, 2020 entitled Compositions and Methods for Increasing Efficacy of a Drug, the contents of which are herein incorporated by reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure provides compositions and methods for increasing the effectiveness of an anti-viral composition against a disease when combined with a mammalian protease inhibitor e.g. a cathepsin inhibitor.
BACKGROUND OF THE DISCLOSURE
[0003] During the drug development process, a vast number of candidate drugs are abandoned because of observed serious adverse reactions. In many cases, these adverse side effects are a result of the large doses required of the intrinsically toxic drug for therapeutic effect when the efficacy of the drug is low. An effective strategy for eliminating the toxicity of these drugs is to lower the required dosage by increasing the drug’s efficacy. Therefore, there is a need for a method for increasing the efficacy of a drug and reducing the required effective dose. The compositions and methods described herein meet this need.
SUMMARY OF THE DISCLOSURE
[0004] The disclosure relates to methods and combinations for increasing the efficacy of a drug in a subject such that the effective dosage is reduced converting the drug into an effective therapeutic composition. In some embodiments, the subject may have a viral infection caused by acoronavirus e.g. SARS-CoV-2, SARS-CoV-1, orMERS-CoV.
[0005] The method comprises combining a drug, such as an antiviral drug or an anticancer drug, with a mammalian protease inhibitor, for example a cathepsin inhibitor. In some embodiments, the drug effective concentration (EC) may be reduced through a potentiating, an additive or a synergistic activity when used in combination with a mammalian protease inhibitor such as a cathepsin inhibitor.
[0006] In one aspect, the present disclosure provides a method for improving the efficacy of a drug thereby reducing the effective dose and reducing toxic effects of the drug, said method comprising combining the drug with a mammalian protease inhibitor, for example a cathepsin inhibitor, such that the combination produces a potentiating, an additive or a synergistic activity enhancing the drug’s effectiveness and reducing the required effective dose or concentration. In some aspects, enhancing the efficacy of a drug by combining it with a mammalian protease inhibitor, for example a cathepsin inhibitor, may result in repurposing the drug for treatment of new indications not previously considered due to the initial low efficacy of the drug.
[0007] In another aspect, the present disclosure provides a method for lowering toxicity of a drug by reducing its effective concentration, comprising combining the drug with a mammalian protease inhibitor, for example a cathepsin inhibitor, such that a potentiating, an additive or a synergistic activity is created enhancing the drug’s effectiveness. In some aspects, lowering toxicity of a drug is achieved by combining it with a mammalian protease inhibitor, for example a cathepsin inhibitor, may result in repurposing the drug for treatment of new indications not previously considered.
[0008] In yet another aspect, the present disclosure provides a method for reducing the effective concentration of a drug in a subject, comprising administering said drug to said subject in combination with a mammalian protease inhibitor, for example a cathepsin inhibitor, such that the combination produces a potentiating, an additive or a synergistic activity thereby reducing the effective concentration of the drug. In some aspects, reducing the effective concentration of a drug by combining it with a mammalian protease inhibitor, for example a cathepsin inhibitor, may result in repurposing the drug for treatment of new indications not previously considered. [0009] Therefore, the disclosure is related to a method and composition comprising a drug combination, the drug combination comprising a drug and a mammalian protease inhibitor, for example a cathepsin inhibitor, that reduces the effective concentration of the drug and therefore the intrinsic toxicity displayed by the drug. Depending on the situation, the active ingredients of this pharmaceutical combination can be administered simultaneously, separately or sequentially. The administration of this pharmaceutical combination can be performed by all possible routes including systemic, topical or oral routes. The pharmaceutical or therapeutic drug combination can be used in the prophylaxis and/or treatment of disease by administering to a subject a therapeutically effective amount of the pharmaceutical combination.
[0010] In one aspect, the present disclosure provides a mixture or combination of a drug and a cathepsin inhibitor for use in the prophylaxis or treatment of disease. In another aspect, the present disclosure provides use of the mixture or combination of the disclosure for preparation of a medicament or a pharmaceutical preparation, whether provided as a combination in one formulation or provided as two separate compounds, whether by similar or different administration methods, concentrations, dosages, or schedules, for the prophylaxis or treatment of disease.
[0011] In another aspect, a drug and cathepsin inhibitor can be combined along with other cathepsin inhibitors, protease inhibitors, proteinase inhibitors or esterase inhibitors for example, a combination with cathepsin inhibitors such as Odanacatib (MK-0822), Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), SLV213 (K777 ORK1777), ,RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV-701,MIV-710, MIV-711,NC- 2300, ORG-219517, ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY-106; VBY-285;VBY-825), VBY-129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV-247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI- 1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY-210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP-0015962), BLD2660, SAR- 164653, KGP94, and VEL-0230, combination with serine protease inhibitors such as Camostat, Odalasvir, Nafamostat mesylate, or any other protease inhibitors currently in use for HIV such as atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), darunavir/cobicistat (Prezcobix) or other protease inhibitors use for other viruses such as HCV for example asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir, or for use in HBV treatment.
[0012] In another aspect, a drug to be combined with a cathepsin inhibitor is an antiviral drug. In yet another aspect, the antiviral drug is a nucleoside analog, a nucleotide analog or a nucleic acid analog, a peptide, a synthetic small molecule, or a large molecule such as those obtained from plant and animal extracts.
[0013] In the case of nucleoside, nucleotide and nucleic acid analogs, their use as antivirals has been hampered due to the high dosage required to produce the antiviral effect, resulting in increased off-target and toxicity in the subject. It was surprisingly discovered that administering a nucleoside analog in combination with a cathepsin inhibitor produced an unexpected synergistic effect, increasing the efficacy of the combination with reduced toxicity and reducing the required dosage of nucleoside analog.
[0014] In one aspect, the disclosure provides a composition comprising a mixture comprising an antiviral drug, for example a nucleotide or nucleoside analog, in combination with a cathepsin inhibitor. The present disclosure provides a method for increasing the efficacy of the antiviral drug by combining it with a cathepsin inhibitor such that the dosage of antiviral drug that must be administered for therapeutic effect is reduced to an amount that is safe and nontoxic.
[0015] In yet another aspect, the antiviral drug is a nucleoside analog or other antiviral, for example, BCX4430 (Galidesivir), T-705 (Avigan, Favipiravir), Brincidofovir, FGE-106, JK-05, Triazavirin, Acyclovir Fleximer, Ribavirin, AL-335 (Adafosbuvir), 6-azauridine, gancyclovir, dideocycytidine, dideoxyinosine, or resimiquid, remdesivir, gemcitabine hydrocholoride, mizoribine, lamivudine, entecavir, telbivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), sofosbuvir, FV100 (FV for FermaVir), letermovir, daclatasvir, asunaprevir, beclabuvir, lopinavir, ritonavir, Hepsera (adefovir dipivoxil), Peveon, Viread (tenofovir disoproxil fumarate), Acycloadenosine (predecessor of acyclovir), NITD008, MK-608, ribonucleoside analog -d-N4- hydroxycytidine (NHC; EIDD- 1931), and EIDD-2801 (Molnupiravir), AT-527, and AT-511. [0016] As a non-limiting example, the nucleoside analog may be T-705 (Avigan, Favipiravir). [0017] In some embodiments, the antiviral drug may be a nucleotide analog.
[0018] In some embodiments, the antiviral drug may be a viral protease inhibitor. As a non- limiting example, the viral protease inhibitor may be PF-07321332, PF-07304814, PF-00835231, atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), darunavir/cobicistat (Prezcobix), asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, or telaprevir.
[0019] In some embodiments, the antiviral drug may be a viral polymerase inhibitor. As a non-limiting example, the viral polymerase inhibitor may be Foscamet, Cidofovir, or Alovudine. [0020] In some embodiments, the antiviral drug may be a reverse transcriptase inhibitor. As a non-limiting example, the reverse transcriptase inhibitor may be Nevirapine, Delavirdine, Efavirenz, Etravirine, Etravirine, Rilpivirine, Adefovir dipivoxil, or Atevirdine.
[0021] In some embodiments, the antiviral drug may be a viral envelope fusion inhibitor. As a non-limiting example, the viral envelope fusion inhibitor may be Docosanol, Enfuvirtide, or Maraviroc.
[0022] In some embodiments, the antiviral drug may be a prophylactic agent such as RSV- IGIV, VZIG, orVariZIG.
[0023] In some embodiments, the antiviral drug may be a protein drug such as an antibody.
[0024] In some embodiments, the antiviral drug may be a proton transport inhibitor. As a non- limiting example, the proton transport inhibitor may be Rimantadine or Methisazone.
[0025] In some embodiments, the antiviral drug may be a neuraminidase inhibitor. As a non- limiting example, the neuraminidase inhibitor may be Zanamivir, Oseltamivir, Laninamivir octanoate, or Peramivir.
[0026] In yet another aspect, the cathepsin inhibitor may be a cathepsin-B inhibitor, a cathepsin- L inhibitor, a cathepsin-S inhibitor, a cathepsin-F inhibitor, a cathepsin-X inhibitor, a cathepsin-K inhibitor, a cathepsin-V inhibitor, a cathepsin-W inhibitor, a cathepsin-C inhibitor, a cathepsin-0 inhibitor, and a cathepsin-H inhibitor. In yet another aspect, the cathepsin inhibitor is a cathepsin-K inhibitor. In another aspect, the cathepsin inhibitor is epoxisuccinate and derivative thereof; or from E-64; E-64a; E-64b; E-64c; E-64d; CA-074; CA-074 Me; CA-030; CA-028; peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac- 5 LVK-CHO, Z-Phe-Tyr- CHO, Z-Phe-Tyr(0tBu)-C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp-CHO, Z-Phe-Leu- C0CH0.H20; peptidyl semicarbazone derivatives; peptidyl methylketone derivatives; peptidyl trifluoromethylketone derivatives Biotin-Phe-Ala fluoromethyl ketone, Z-Leu-Leu-Leu- fluoromethyl ketone, Z-Phe-Phe-fluoromethyl ketone, NMethoxysuccinyl-Phe-HOMO-Phe- fluoromethyl ketone, Z Leu- Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone; peptidylchloromethases and derivatives thereof; peptidylhydroxymates and derivatives thereof; peptidylhydroxylamines and derivatives thereof; peptidyl acyloxymethanes and derivatives thereof; peptidylacyloxymethyl ketones and derivatives thereof; peptidyl aziridines and derivatives thereof; peptidyl aryl vinyl sulfones and derivatives thereof; peptidyl arylvinylsulfonates and derivatives thereof; gallinamide analogs and derivates thereof; peptidyl aldehydes and derivatives thereof; azepinone-based inhibitors and derivatives thereof; nitrile- containing inhibitors and derivates thereof; thiosemicarbazone and derivatives thereof; propeptide mimics and derivatives thereof; thiocarbazate, oxocarbazate, azapaptides and derivatives thereof; peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ-Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala-CHN2, Z-Phe-Thr(OBzl)- CHN2, Z-Phe-Tyr (Ot-But)-CHN2, Z-Leu-Leu-Tyr-CHN2; peptidyl acyloxymethyl ketones; peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS; peptidyl nitriles; peptidyl disulfides, 5,5'-dithiobis[2- nitrobenzoic acid], cysteamines, 2,2'-dipyridyl disulfide; non- covalent inhibitors, N-(4-Biphenylacetyl)-S-methyl cysteine-(D)-Arg-Phe-b- 5 phenethylamide; thiol alkylating agents, maleimides, etc; azapeptides; azobenzenes; O-acylhydroxamates, Z-Phe- Gly-NHO-Bz, Z-FG-NHO-BzOME; lysosomotropic agents, chloroquine, ammonium chloride; inhibitors based on Cystatins A, B, C, D, F, stefins, kininogens, Sialostain L, antimicrobial peptide LL-37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50; Odanacatib (MK-0822), Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), SLV213 (K777 OR K1777), RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV-15 701,MIV-710, MIV- 711,NC-2300, ORG-219517,ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY- 106; VBY-285;VBY- 825), VBY- 129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV-20247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI- 1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY- 210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP-25 0015962), SAR-164653, VEL-0230, KGP94, and BLD2660.
[0027] Other cathepsin inhibitors are described in Dana et al., 2020. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 25: 698, incorporated herein by reference thereto.
[0028] In one aspect, the disclosure provides a composition and method for prophylaxis or treatment of a disease comprising administering in a pharmaceutically effective amount to a subject in need, e.g. a human patient, an antiviral drug, e.g. a nucleoside analog, in combination with a cathepsin inhibitor, such that the drug’s efficacy is increased, or a synergistic activity is produced, thereby reducing the effective dose of the drug along with its intrinsic toxicity.
[0029] In one aspect, the disease is a viral infection. In another aspect, the disease is one or more of cancer, tumor growth, sarcomas, metastasis, osteoporosis, osteoarthritis, atherosclerosis, hypertension, any endothelial related abnormality, systemic lupus erythemotosis, lupus nephritis, peripheral vascular disease, stroke, coronary heart disease, diabetes, insulin resistance, kidney failure, and/or venous thrombosis.
[0030] In another aspect, the viral infection is caused by a coronavirus, Orthomyxoviridae, influenza A virus, influenza B virus, influenza C virus, Thogotovirus, Dhori virus, infectious salmon anemia virus, Paramyxoviridae, parainfluenza virus, human respiratory syncytial virus (RSV), Sendai virus, Newcastle disease virus, mumps virus, rubeola (measles) virus, Hendra virus, Nipah virus, avian pneumovirus, canine distemper virus, Rhabdoviridae rabies virus, vesicular stomatitis virus (VSV), Mokola virus, Duvenhage virus, European bat virus, salmon infectious hematopoietic necrosis virus, viral hemorrhagic septicaemia virus, spring viremia of carp virus, and snakehead rhabdovirus, Bomaviridae, Boma disease virus, Bunyaviridae Bunyamwera virus, Hantaan virus, Crimean Congo virus, California encephalitis virus, Rift Valley fever virus, and sandfly fever virus, Arenaviridae Old World Arenaviruses, Lassa virus, Ippy virus, Lymphocytic choriomeningitis virus (LCMV), Mobala virus, Mopeia virus, New World Arenaviruses, Junin virus (Argentine hemorrhagic fever), Sabia (Brazilian hemorrhagic fever), Amapari virus, Flexalvirus, Guanarito virus (Venezuela hemorrhagic fever), Machupo virus (Bolivian hemorrhagic fever), Latino virus, Boliveros virus, Parana virus, Pichinde virus, Pirital virus, Tacaribe virus, Tamiami virus, Whitewater Arroyo virus, arboviruses togaviruses, Alphaviruses, Venezuela equine encephalitis virus, Sindbis virus, Rubivirus, Rubella virus, Flaviviridae, flavivirus, Pestivirus, and Hepacivirus, yellow fever virus, dengue fever virus, and Japanese encaphilitis (JE) virus, Pestivirus, Hepacivirus, hepatitis C virus, hepatitis C-like viruses, Japanese encephalitis Alfiiy, Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley encephalitis, St. Louis encephalitis, Stratford, Usutu, West Nile viruses,
Pestivirus, bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV), border disease virus (BDV), Arenaviridae, Lymphocytic choriomeningitis virus (LCMV), Lassa virus, Junin virus, Machupo virus, Guanarito virus, Sabia, Phlebovirus Rift valley fever virus, Hendra, Nipah, Riboviria, coronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV.
[0031] In yet another aspect, the viral infection is caused by a coronavirus. In yet another aspect, the coronavirus is SARS-CoV, MERS-CoV, SARS-CoV-2, or any related viruses with positive or negative strand amplification with or without protective envelope.
[0032] In another aspect, the disclosure provides a composition and method for prophylaxis or treatment of a coronavirus infection such as SARS-CoV, MERSCoV, SARS-CoV-2, or any related viruses with positive or negative strand amplification with or without protective envelope, comprising administering in a pharmaceutically effective amount to a subject in need, e.g. a human patient, a cathepsin inhibitor in combination with an antiviral drug. In one aspect, the cathepsin inhibitor is a cathepsin-K inhibitor or a cathepsin-L inhibitor.
[0033] In another aspect, the disclosure provides a combination of one or more antiviral drug and one or more cathepsin inhibitor for treatment of an viral infection, where the antiviral drug is one or more drugs such as, but not limited to, BCX4430 (Galidesivir), T-705 (Avigan, Favipiravir), Brincidofovir, FGE-106, JK-05, Triazavirin, Acyclovir Fleximer, Ribavirin, AL- 335 (Adafosbuvir), 6-azauridine, gancyclovir, dideocycytidine, dideoxyinosine, or resimiquid, remdesivir, gemcitabine hydrocholoride, mizoribine, lamivudine, entecavir, telbivudine, adefovir dipivoxil, tenofovir disoproxil fiimarate (TDF), sofosbuvir, FV100 (FV for FermaVir), letermovir, daclatasvir, asunaprevir, beclabuvir, lopinavir, ritonavir, Hepsera (adefovir dipivoxil), Peveon, Viread (tenofovir disoproxil fiimarate), Acycloadenosine (predecessor of acyclovir), NITD008, MK-608, ribonucleoside analog b-ά-N4- hydroxycytidine (NHC; EIDD-1931), and EIDD-2801 (Molnupiravir), AT-527, and AT-511, and where the cathepsin inhibitor is one or more cathepsin inhibitor chosen from a cathepsin-B inhibitor, a cathepsin-L inhibitor, a cathepsin-S inhibitor, a cathepsin-F inhibitor, a cathepsin-X inhibitor, a cathepsin-K, inhibitor, a cathepsin-V inhibitor, a cathepsin-W inhibitor, a cathepsin-C inhibitor, a cathepsin-0 inhibitor, and a cathepsin- H inhibitor. In yet another aspect, the cathepsin inhibitor is a cathepsin-K inhibitor. In another aspect, the cathepsin inhibitor is epoxisuccinate and derivative thereof; E-64; E-64a; E-64b; E-64c; E-64d; CA-074; CA-074 Me; CA-030; CA-028; peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac-LVK-CHO, Z-Phe-Tyr-CHO, Z-Phe- Tyr(0tBu)-C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp- CHO, Z-Phe-Leu-C0CH0.H20; peptidyl semicarbazone derivatives; peptidyl methylketone derivatives; peptidyl trifluoromethylketone derivatives Biotin- Phe-Ala-fluoromethyl ketone, Z-Leu-Leu-Leu- fluoromethyl ketone, Z-Phe-Phe-fluoromethyl ketone, N-Methoxysuccinyl-Phe-HOMO-Phe- fluoromethyl ketone, Z-Leu-Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone; peptidylchloromethases and derivatives thereof; peptidylhydroxymates and derivatives thereof; peptidylhydroxylamines and derivatives thereof; peptidyl acyloxymethanes and derivatives thereof; peptidylacyloxymethyl ketones and derivatives thereof; peptidyl aziridines and derivatives thereof; peptidyl aryl vinyl sulfones and derivatives thereof; peptidyl arylvinylsulfonates and derivatives thereof; gallinamide analogs and derivates thereof; peptidyl aldehydes and derivatives thereof; azepinone-based inhibitors and derivatives thereof; nitrile- containing inhibitors and derivates thereof; thiosemicarbazone and derivatives thereof; propeptide mimics and derivatives thereof; thiocarbazate, oxocarbazate, azapaptides and derivatives thereof; peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ-Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala-CHN2, Z-Phe-Thr(OBzl)- CHN2, Z-Phe-Tyr (Ot- But)-CHN2, Z-Leu-Leu-Tyr-CHN2; peptidyl acyloxymethyl ketones; peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS; peptidyl nitriles; peptidyl disulfides, 5,5'-dithiobis[2-nitrobenzoic acid], cysteamines, 2,2'-dipyridyl disulfide; non-covalent inhibitors, N-(4-10 Biphenyl acetyl)-S-methyl cysteine-(D)-Arg-Phe-b-phenethylamide; thiol alkylating agents, maleimides, etc; azapeptides; azobenzenes; O-acylhydroxamates, Z-Phe-Gly- NHO-Bz, Z-FG-NHO-BzOME; lysosomotropic agents, chloroquine, ammonium chloride; inhibitors based on Cystatins A, B, C, D, F, stefins, kininogens, Sialostain L, antimicrobial peptide LL-37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50; Odanacatib (MK-0822), Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), SLV213 (K777 OR K1777), ,RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV- 701,MIV-710, MIV- 711,NC-2300, ORG-219517,ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY- 106; VBY-285;VBY- 825), VBY- 129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV- 247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI- 1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY- 210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP-0015962), SAR-164653, VEL-0230, KGP94, and BLD2660.
[0034] In another aspect, the present disclosure provides a composition and method for the treatment of viral infection, the composition comprising one or more cathepsin inhibitor chosen from cathepsin inhibitor is one or more cathepsin inhibitor chosen from a cathepsin-B inhibitor, a cathepsin-L inhibitor, a cathepsin-S inhibitor, a cathepsin-F inhibitor, a cathepsin-X inhibitor, a cathepsin-K, inhibitor, a cathepsin-V inhibitor, a cathepsin-W inhibitor, a cathepsin-C inhibitor, a cathepsin-0 inhibitor, and a cathepsin-H inhibitor. In yet another aspect, the cathepsin inhibitor is a cathepsin-K inhibitor. In another aspect, the cathepsin inhibitor is epoxisuccinate and derivative thereof; E-64; E-64a; E-64b; E-64c; E-64d; CA-074; CA-074 Me; CA-030; CA-028; peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac-LVK-CHO, Z-Phe-Tyr-CHO, Z-Phe- Tyr(0tBu)-C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp-CHO, Z-Phe-Leu-C0CH0.H20; peptidyl semicarbazone derivatives; peptidyl methylketone derivatives; peptidyl trifluoromethylketone derivatives Biotin-Phe-Ala-fluoromethyl ketone, Z-Leu-Leu-Leu- fluoromethyl ketone minimum, Z-Phe-Phe-fluoromethyl ketone, N25 Methoxysuccinyl-Phe- HOMO-Phe-fluoromethyl ketone, ZLeu- Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone; peptidylchloromethases and derivatives thereof; peptidylhydroxymates and derivatives thereof; peptidylhydroxylamines and derivatives thereof; peptidyl acyloxymethanes and derivatives thereof; peptidylacyloxymethyl ketones and derivatives thereof; peptidyl aziridines and derivatives thereof; peptidyl aryl vinyl sulfones and derivatives thereof; peptidyl arylvinylsulfonates and derivatives thereof; gallinamide analogs and derivates thereof; peptidyl aldehydes and derivatives thereof; azepinone-based inhibitors and derivatives thereof; nitrile-containing inhibitors and derivates thereof; thiosemicarbazone and derivatives thereof; propeptide mimics and derivatives thereof; thiocarbazate, oxocarbazate, azapaptides and derivatives thereof; peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ-Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala-CHN2, Z-Phe-Thr(OBzl)- CHN2, Z-Phe-Tyr (Ot- But)-CHN2, Z-Leu-Leu-Tyr-CHN2; peptidyl acyloxymethyl ketones; peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS; peptidyl nitriles; peptidyl disulfides, 5,5'-dithiobis[2-nitrobenzoic acid], cysteamines, 2,2'-dipyridyl disulfide; non-covalent inhibitors, N-(4-Biphenylacetyl)-S-methylcysteine-(D)-Arg-Phe-bphenethylamide; thiol alkylating agents, maleimides, etc; azapeptides; azobenzenes; O-acylhydroxamates, Z-Phe-Gly- NHO-Bz, Z-FG-NHO-BzOME; lysosomotropic agents, chloroquine, ammonium chloride; inhibitors based on Cystatins A, B, C, D, F, stefins, kininogens, Sialostain L, antimicrobial peptide LL-37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50; Odanacatib (MK-0822), Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), SLV213 (K777 or K1777), RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV- 701,MIV-710, MIV- 711,NC-2300, ORG-219517,ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, 30 VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY-106; VBY- 285;VBY-825), VBY-129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY- 3000328, MIV-247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI-1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY-210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP- 0962 (EVP-0015962), KGP94, SAR-164653, and VEL-0230, and BLD2660. Examples of other cathepsin inhibitors are described in Dana et al., 2020. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 25: 698. All references cited are herein incorporated in their entirety by reference thereto.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] The foregoing and other objects, features and advantages will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings. The drawings are not necessarily to scale; emphasis instead being placed upon illustrating the principles of various embodiments of the invention [0036] Figure l is a graph predicting the effect of adding a cathepsin inhibitor to an antiviral drug. The cathepsin inhibitor is expected to enhance the antiviral activity of the compound by more than a log. The large arrow shows the expected shift in the effective concentration (EC50) of the antiviral drug. The vertical dotted line shows the expected cytotoxicity of the drug at EC 50 with or without the cathepsin inhibitor.
DETAILED DESCRIPTION OF THE DISCLOSURE I. INTRODUCTION
[0037] During the drug development process, a vast number of candidate drugs are abandoned because of observed serious adverse reactions. In many cases, these adverse side effects are a result of the large doses required of the intrinsically toxic drug for therapeutic effect when the efficacy of the drug is low. An effective strategy for eliminating the toxicity of these drugs is to lower the required dosage by increasing the drug’s efficacy. Therefore, there is a need for a method for increasing the efficacy of a drug and reducing the required effective dose. The compositions and methods described herein meet this need.
[0038] Provided herein are compositions comprising a drug and/or a mammalian protease inhibitor. In some embodiments, the combination of the mammalian protease inhibitor with the drug produces a synergistic activity. The synergistic activity of the mammalian protease inhibitor with the drug may be result in a reduction of the effective dose of the drug required to produce a desired effect. The reduced dose in turn may lower the toxicity associated with the drug. In some embodiments, the drug is an antiviral drug.
[0039] The present disclosure provides methods wherein a composition provides an increase in bioavailability of a drug combined with a mammalian protease inhibitor, for example a cathepsin inhibitor, as measured by AUC of at least 25% relative to dosing of the drug alone. The present disclosure also provides methods wherein the composition provides an increase in bioavailability of the drug combination as measured by AUC of at least 50% relative to dosing of the drug alone. The present disclosure further provides methods wherein said composition provides an increase in bioavailability of the drug in combination as measured by AUC of at least 100% relative to dosing of the drug alone. The disclosure provides a composition that increases the bioavailability of the drug when in combination with a mammalian protease inhibitor, for example a cathepsin inhibitor, as measured by Cmax of at least 50% relative to dosing of the drug alone. Changes in the integrated systemic concentrations overtime are indicated by area under the curve (AUC) or Cmax, both parameters well known in the art. AUC is a determination of the Area Under the Curve plotting the serum or plasma concentration of drug along the ordinate (Y -axis) against time along the abscissa (X-axis). Generally, the values for the AUC represent drug concentrations over time in units of mass-time/volume. When efficacy of a drug is being measured, the amount and form of the drug administered should be the same in both the administration of the drug in combination with the mammalian protease inhibitor, for example a cathepsin inhibitor, or the administration of the drug alone.
[0040] The disclosure also provides said composition that increases the bioavailability of the drug when used in combination as measured by Cmax of at least 100% relative to dosing of the drug alone. The disclosure further provides said composition which provides an increase in bioavailability of the drug when used in combination as measured by Cmax of at least 200% relative to dosing of drug alone. Systemic drug concentrations are measured using standard biochemical drug measurement techniques (Simmons et al., Anal Uett. 39: 2009-2021 (1997); the contents of which are herein incorporated by reference in its entirety).
[0041] The present disclosure provides a composition that increases clearance of the drug when used in combination with a mammalian protease inhibitor, for example a cathepsin inhibitor, from normal tissues as measured by pharmacological studies of at least 25% relative to dosing of the drug alone. It also provides a composition that increases in clearance of the drug in combination from normal tissues as measured by pharmacokinetic studies of at least 50% relative to dosing of the drug alone. It further provides said composition that increases in clearance of the drug in combination from normal tissues as measured by pharmacokinetic studies of at least 100% relative to dosing of the drug alone. Clearance of drug normally occurs from the liver and kidneys and it is assumed that only free and not protein bound, drug is available for clearance.
For hepatic clearance, passive diffusion through the lipid core of the hepatocyte membranes, available to lipophilic drugs, is augmented by sinusoidal carrier systems particularly for ionized molecules (anionic and cationic) of molecular weights of approximately 3-400. Uikewise other transporters on the canalicular face transport drugs or their metabolites into bile. This system has two separate processes, hepatic uptake and biliary excretion. With small sized lipophilic drugs that readily traverse membranes hepatic uptake is not a major factor, but with higher molecular weight compounds (above 500) and those containing considerable H-bonding hepatic uptake can become the key clearance process, even if metabolism occurs subsequent to this.
[0042] When a drug rapidly dissolves and readily crosses the intestinal membranes, absorption tends to be complete, but absorption of orally administered drugs is not always complete. Before reaching the vena cava, a drug must move down the gastrointestinal tract and pass through the gut wall and liver, common sites of drug metabolism. Thus a drug may be metabolized during first-pass metabolism before it can be measured in the systemic circulation. Many drugs have low oral bioavailability because of expensive first-pass metabolism.
[0043] Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. More factors can affect bioavailability when absorption is slow or incomplete than when it is rapid and complete. That is, slow or incomplete absorption leads to variable therapeutic responses. Slow absorption in the gastrointestinal tract also leads to increased acute and delayed-phase chemotherapy induced nausea and vomiting.
[0044] Insufficient time in the gastrointestinal tract is a common cause of low bioavailability. Ingested drug is exposed to the entire gastrointestinal tract for no more than one to two days and to the small intestine for only 2 to 4 hours. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (e.g., if it is highly ionized and polar), time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, activity, genetic phenotype, stress, disease or previous gastrointestinal surgery can affect drug bioavailability.
[0045] Reactions that compete with absorption can reduce bioavailability. They include complex formation, hydrolysis by gastric acid or digestive enzymes, conjugation in the gut wall, absorption of other drugs and metabolism by luminal micro flora.
[0046] Assessment of bioavailability from plasma concentration-time data usually involves determining maximum peak concentration, the time at which maximum peak plasma drug concentration occurs, and the area under the plasma concentration time curve (AUC). The plasma drug concentration increases with the extent of absorption. The peak is reached when the drug elimination rate equals absorption rate. AUC is the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation. [0047] Drug products may be considered bioequivalent in extent and rate of absorption if their plasma level curves are essentially super imposable. Drug products that have similar AUCs but differently shaped plasma level curves are equivalent in extent but differ in their absorption rate time profdes. Absorption occurs by one of three methods, either passive diffusion, active transport or facilitated active transport. Passive diffusion is simply the passage of molecules across the mucosal barrier until the concentration of molecules reaches osmotic balance on both sides of the membrane. In active transport the molecule is actively pumped across the mucosa. In facilitated transport, a carrier generally a protein, is required to convey the molecule across the membrane for absorption.
II. COMPOSITIONS OF THE DISCLOSURE
[0048] The word “drug” as used herein is defined as a chemical intended for use in the treatment or prevention of disease. Drugs include synthetic and naturally occurring bio affecting substances as well as recognized pharmaceuticals, such as those listed in “The Physician desk Reference,” 56th ed, pages 101-133 (or an updated edition). These references are incorporated by reference herein. The term “drug” also includes similar drugs that have the indicated properties that are not discovered or available. The present disclosure provides drugs consisting of charged, uncharged, hydrophilic, zwitter-ionic, or hydrophobic species, as well as any combinations of these physical characteristics. A hydrophobic drug is defined as a drug which in its non-ionized form is more soluble in lipid or fat than in water. A preferred class of hydrophobic drugs is those drugs that are more soluble in octanol than in water.
Antiviral drugs
[0049] In some embodiments, the drug is an antiviral drug.
[0050] Antiviral drugs may be used for treating viral infections by inhibiting their entry into the cell, or inhibiting viral development by blocking viral RNA or DNA synthesis. Antiviral drugs of the present disclosure may be, for example, 5-substituted 2'-deoxyuridine analogues nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, viral protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside, and/or phosphonate analogues.
[0051] In some embodiments, the compositions of the disclosure may include antivirals drugs currently in use for the treatment of HIV such as, but not limited to, atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), darunavir/cobicistat (Prezcobix) or other protease inhibitors use for other viruses such as HCV for example Asunaprevir, Boceprevir, Grazoprevir, Glecaprevir, Paritaprevir, Simeprevir, and/or Telaprevir. Nucleotide analogs
[0052] In some embodiments, the compositions of the disclosure may include nucleotide analogs which are synthetic compounds which are similar to nucleotides, but which have an incomplete or abnormal deoxyribose or ribose group. Once the nucleotide analogs are in the cell, they are phosphorylated, producing the triphosphate formed which competes with normal nucleotides for incorporation into the viral DNA or RNA. Once the triphosphate form of the nucleotide analog is incorporated into the growing nucleic acid chain, it causes irreversible association with the viral polymerase and thus chain termination, thereby blocking viral replication by impairing DNA/RNA synthesis or by inhibiting cellular or viral enzymes involved in nucleoside/tide metabolism. A description of nucleotide analogs, their structure and function is found in the following references incorporated by reference thereto: Eyer et al., 2018, Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses. Antiviral Chemistry and Chemotherapy 26, 1-28 (the contents of which are herein incorporated by reference in its entirety).
Nucleoside analogs
[0053] In some embodiments, the compositions of the disclosure may include nucleoside analogs. The antiviral effects and their pharmacokinetic properties make some nucleoside analogs suitable for the treatment of acute infections caused by medically important RNA and DNA viruses. Many small molecule-based antivirals are nucleoside analogs, most commonly used for chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. There are currently over 25 approved therapeutic nucleosides used in therapy of various diseases ranging from viral infections to osteoporosis, to cancer. Non-limiting examples of nucleoside analogs include, BCX4430 (Galdisivir), T-705 (Favipiravir, Avigan), JNJ- 64041575, JNJ-1575, ALS-008176, AL-8176 (Lumicitabine), Brincidofovir, Camostat, Odalasvir, FGE-106, JK-05, Nafamostat mesylate, Triazavirin, Acyclovir Fleximer and other Fleximers, Ribavirin, AF-335 (Adafosbuvir), 6-azauridine, Acyclovir, gancyclovir, idoxuridine, dideoxyinosine, dideoxycytidine, zidovudine (azidothymidine), imiquimod, resimiquimod, remdesivir, gemcitabine hydrocholoride, mizoribine, lamivudine, entecavir, telbivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), sofosbuvir, FV100 (FV for FermaVir), letermovir, daclatasvir, asunaprevir, beclabuvir, lopinavir, ritonavir, Hepsera (adefovir dipivoxil), Peveon, Viread (tenofovir disoproxil fumarate), Acycloadenosine (predecessor of acyclovir), NITD008, MK-608, ribonucleoside analog -d-N4-hydroxycytidine (NHC; EIDD-1931), EIDD-2801 (Molnupiravir), AT-527, and AT-511. As the methods and compositions of the disclosure provide synergistic activity in these drugs, these analogs can potentially be repurposed for treatment of other infections and diseases.
[0054] In some embodiments, the nucleoside analog may be Trifluridine, Brivudine, Vidarabine (Vidarabine Phosphate, Vidarabine Sodium Phosphate), Tellbivudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Sorivudine, Fialuridine, Fiacitabine.
Additional antiviral drugs
[0055] Other anti -viral drugs may be combined with the protease inhibitors e.g. cathepsin inhibitors of the disclosure. Examples of additional antiviral drugs include but are not limited to immunoglobulins, amantadine, interferons. Examples of anti-viral agents include, but are not limited to, Idoxuridine , Trifluridine Brivudine, Vidarabine, Entecavir, Tellbivudine, Foscamet, Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Lamivudine in combination with zidovudine, Abacavir, Abacavir in combination with lamivudine and zidovudine, Emtricitabine, Nevirapine, Delavirdine, Efavirenz, Etravirine, Etravirine, Rilpivirine, Saquinavir, Ritonavir, Indinavir, Nelfmavir, Amprenavir, Lopinavir- ritonavir, Atazanavir, Tipranavir, Darunavir, Darunavir in combination with cobicistat, Atazanavir in combination with cobicistat, Telaprevir, Boceprevir, Simeprevir, Asunaprevir, Vaniprevir in combination with ribavirin and PeglFNox- 2b, Paritaprevir, Paritaprevir, Grazoprevir, Raltegravir, Elvitgravir, Dolutegravir, Dolutegravir in combination with abacavir and lamivudine, Dolutegravir in combination with lamivudine, RSV- IGIV, Palvizumab, Docosanol, Enfuvirtide, Maraviroc, VZIG, VariZIG, Acyclovir, Ganciclovir, Famciclovir, Valacyclovir, Penciclovir, Valganciclovir, Cidofovir, Tenofovir disoproxil fumarate, Adefovir dipivoxil , Tenofovir disoproxil fumarate in combination with emtricitabine , Tenofovir disoproxil fumarate in combination with efavirenz and emtricitabine, Tenofovir disoproxil fumarate in combination with rilpivirine and emtricitabine, Tenofovir disoproxil fumarate in combination with cobicistat and Elvitegravir, Tenofovir alafenamide in combination with cobicistat , emtricitabine and elvitegravir, Tenofovir alafenamide in combination with rilpivirine and emtricitabine, Tenofovir alafenamide in combination with emtricitabine, Sofosbuvir in combination with ribavirin, Sofosbuvir in combination with ribavirin and PegIFNox , Daclatasvir in combination with asunaprevir, Ledipasvir in combination with sofosbuvir, Sofosbuvir in combination with simeprevir, Ombitasvir in combination with dasabuvir , paritaprevir and ritonavir, Ombitasvir in combination with paritaprevir and ritonavir, Daclatasvir in combination with sofosbuvir, Elbasvir in combination with grazoprevir, Amantadine , Ribavirin, AL-335 30 (Adafosbuvir), Rimantadine, Rimantadine, Zanamivir, Olseltamivir, Laninamivir octanoate, Laninamivir octanoate, Peramivir, Favipiravir, Pegylated interferon alfa 2b, Interferon alfacon , Pegylated interferon alfa 2b in combination with ribavirin, Pegylated interferon alfa 2a, Fomivirsen, Podofdox, Imiquimod , Sinecatechins, Acemanan, Acyclovir Sodium, Alovudine, Alvircept Sudotox, Amantadine Hydrochloride, Alvircept Sudotox, Amantadine Hydrochloride, Aranotin, Arildone, Aegirine Mesylate, Avridine, Cidofovir, Cipamfylline, Cytarabine Hydrochloride, Delavirdine Mesylate, Desciclovir, Didanosine, Disoxaril Edoxudine, Enviradene, Enviroxime, Famciclovir, Famotine Hydrochloride, Fiacitabine, Fialuridine, Fosarilate, Foscamet Sodium, Fosfonet Sodium, Ganciclovir, Ganciclovir Sodium, Idoxuridine, Kethoxal, Lamivudine, Lobucavir, Memotine Hydrochloride, Methisazone, Nevirapine, Penciclovir, Pirodavir, Ribavirin, AL-335 (Adafosbuvir), Rimantadine Hydrochloride, Saquinavir Mesylate, Somantadine Hydrochloride, Sorivudine, Statolon, Stavudine, Tilorone Hydrochloride, Trifluridine, Valacyclovir Hydrochloride, Vidarabine, Vidarabine Phosphate , Vidarabine Sodium Phosphate, Viroxime, Zalcitabine , Zidovudine, and/or Zinviroxime.
Viral protease inhibitors
[0056] In some embodiments, the antiviral drug is a viral protease inhibitor. As used herein a protease inhibitor is a molecule that blocks or reduces the activity of a protease. Proteases are essential for virus replication. Specifically, a viral protease inhibitor refers to a protease inhibitor that is capable of targeting and reducing the activity of a viral protease.
[0057] In some embodiments, the viral protease inhibitor may be a viral serine protease inhibitor, such as, but not limited to, Camostat, Odalasvir, Femostat, or any other protease inhibitors currently in use for HIV such as atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), darunavir/cobicistat (Prezcobix) or other protease inhibitors use for other viruses such as HCV for example asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir, and in HBV treatment, may be useful in the present disclosure.
[0058] In some embodiments, the protease inhibitor may a viral protease inhibitor. Viral proteases such as SARS-CoV proteases are essential for viral life-cycle and these proteases can be inhibited by compounds such as, but not limited to, PF-07321332, PF-07304814, and PF- 00835231.
[0059] In some embodiments, the viral protease inhibitor may be Indinavir, Nelfmavir, Saquinavir (Saquinavir Mesylate), Ritonavir, Amprenavir, Lopinavir, ritonavir, Atazanavir, Tipranavir, Darunavir, Telaprevir, Boceprevir, Simeprevir, Asunaprevir, Vaniprevir in combination with ribavirin, Paritaprevir, Paritaprevir, Grazoprevir, Ganciclovir (Ganciclovir Sodium), Famciclovir, Valacyclovir (Valacyclovir Hydrochloride), Penciclovir, and/or Valganciclovir.
Viral polymerase inhibitors
[0060] In some embodiments, the antiviral drug may be a polymerase inhibitor. Non-limiting examples of viral polymerase inhibitors include Foscamet (Foscamet Sodium, Fosfonet Sodium), Cidofovir, and/or Alovudine.
Reverse transcriptase inhibitors
[0061] In some embodiments, the antiviral drug may be a reverse transcriptase inhibitor. Non limiting examples of reverse transcriptase enzyme inhibitors include, Nevirapine, Delavirdine (Delavirdine Mesylate), Efavirenz, Etravirine, Rilpivirine, Adefovir dipivoxil, and/or Atevirdine. Viral integrase inhibitors
[0062] In some embodiments, the antiviral drug may be a viral integrase inhibitor. Non- limiting examples of integrase inhibitor include, Raltegravir, Elvitegravir, and/or Dolutegravir. Viral envelope fusion inhibitors
[0063] In some embodiments, the antiviral drug may be an agent that inhibits the fusion of the viral envelope with the host cell membrane. Non-limiting examples of viral envelope fusion inhibitors include Docosanol, Enfuvirtide, and/or Maraviroc.
Prophylactic agents
[0064] In some embodiments, the antiviral drug may be a prophylactic agent such as a vaccine. Non-limiting examples of vaccines include, RSV-IGIV, VZIG, and/or VariZIG.
Protein drugs
[0065] In some embodiments, the antiviral drug may be a protein drug. As used herein, a protein drug refers to a drug having protein characteristics including large molecular weight. In some embodiments, the drug may be an antibody. Non-limiting examples of antibodies include Palvizumab, Atoltivimab, maftivimab, odesivimab, and/or Zmapp.
[0066] In some embodiments, the protein drug may be pegylated interferon alfa 2b, interferon alfacon, and/or a pegylated interferon alfa 2a. Proton transport inhibitors
[0067] In some embodiments, the antiviral drug is a proton transport inhibitor. Non-limiting examples of proton transport inhibitors include Rimantadine (Rimantadine Hydrochloride), and/or Methisazone.
Neuraminidase inhibitors
[0068] In some embodiments, the antiviral drug is a neuraminidase inhibitor. Non-limiting examples of neuraminidase inhibitors include, Zanamivir, Oseltamivir, Laninamivir octanoate, Laninamivir octanoate, and/or Peramivir.
Antiviral drug combinations
[0069] In some embodiments, the compositions of the disclosure may include two or more antiviral drugs. Non-limiting examples of antiviral drugs combinations include, Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate in combination with emtricitabine , Tenofovir disoproxil fumarate in combination with efavirenz and emtricitabine, Tenofovir disoproxil fumarate in combination with rilpivirine and emtricitabine, Tenofovir disoproxil fumarate in combination with cobicistat and Elvitegravir, Tenofovir alafenamide in combination with cobicistat , emtricitabine and elvitegravir, Tenofovir alafenamide in combination with rilpivirine and emtricitabine, Tenofovir alafenamide in combination with emtricitabine, Sofosbuvir in combination with ribavirin, Sofosbuvir in combination with ribavirin and PegIFNox , Daclatasvir in combination with asunaprevir, Ledipasvir in combination with sofosbuvir, Sofosbuvir in combination with simeprevir, Ombitasvir in combination with dasabuvir , paritaprevir and ritonavir, Ombitasvir in combination with paritaprevir and ritonavir, Daclatasvir in combination with sofosbuvir, Elbasvir in combination with grazoprevir, Dolutegravir in combination with abacavir and lamivudine, Dolutegravir in combination with lamivudine, Pegylated interferon alfa 2b in combination with ribavirin, Abacavir in combination with lamivudine and zidovudine, Darunavir in combination with cobicistat, Atazanavir in combination with cobicistat.
Other antiviral drugs
[0070] In some embodiments, antiviral drugs of the disclosure may be Amantadine, AL-335, Podofdox, Imiquimod, Sinecatechins, Acemanan, Statolon, Somantadine Hydrochloride, Pirodavir, Memotine Hydrochloride, Lobucavir, Kethoxal, Fosarilate, Famotine, Enviroxime, Enviradene, Disoxaril Edoxudine, Desciclovir, Cytarabine Hydrochloride, Cipamfylline, Avridine, Arildone, Tilorone Hydrochloride, Viroxime, Zalcitabine, Fomivirsen and/or Zinviroxime. Protease inhibitors
[0071] In some embodiments, the compositions of the disclosure may include a protease inhibitor. As used herein a protease inhibitor is a molecule that blocks or reduces the activity of a protease. Proteases are essential for virus replication. Many human pathogenic viruses use human enzymes to activate the viral proteins and successfully overtake the infected cell processes.
[0072] Proteases may be grouped according to the key catalytic group in the active site. For example, the active site of the protease may include a serine (Ser), a threonine (Thr), a cysteine (Cys), an aspartate (Asp), a glutamate (Glu), or a zinc in the case of metalloproteases. Accordingly the proteases may be a serine protease, a threonine protease, a cysteine protease, an aspartate protease, a glutamate protease, or a zinc protease.
[0073] In one embodiment, the protease may be a mammalian protease and the inhibitor may be a mammalian protease inhibitor. In aspect, the mammalian protease may be a cathepsin protease and the inhibitor may be a cathepsin protease inhibitor.
[0074] Human cathepsins assist in the cleavage of viral proteins that are essential for the virus life cycle. These proteases would include, but are not limited to, cysteine proteases and proteinases, serine proteases, aspartic proteases.
[0075] In some embodiments, the mammalian protease inhibitor may be a cathepsin inhibitor. As used herein, a “cathepsin inhibitor” is an agent whose pharmacological effect is to inhibit the activity of the class of endosomal cysteine proteases that require acidic pH for enzyme activity.
In some embodiments, the cathepsin may be a cysteine protease and is herein referred to as a cysteine cathepsin. Examples of human cysteine cathepsin proteases include, but are not limited to, cathepsins, which include but are not limited to cathepsin B, cathepsin L, cathepsin S, cathepsin F, cathepsin X, cathepsin K, cathepsin V, cathepsin W, cathepsin C, cathepsin O, and cathepsin H. Cathepsin inhibitors useful in non-human animals are often categorized differently but are known to those of skill in the art. Thus, the inhibitors include cathepsin inhibitors which are known to correspond with human cathepsin inhibitors. Inhibitors of these cathepsins, are useful according to methods of the disclosure. Many cathepsin inhibitors have been described in the literature and are well known and many are commercially available.
[0076] In one embodiment of the disclosure, the cysteine protease inhibitor is a cathepsin inhibitor such as a cathepsin inhibitor is one or more cathepsin inhibitor chosen from a cathepsin- B inhibitor, a cathepsin-L inhibitor, a cathepsin-S inhibitor, a cathepsin-F inhibitor, a cathepsin-X inhibitor, a cathepsin-K, inhibitor, a cathepsin-V inhibitor, a cathepsin-W inhibitor, a cathepsin-C inhibitor, a cathepsin-0 inhibitor, and a cathepsin- H inhibitor. In yet another aspect, the cathepsin inhibitor is a cathepsin-K inhibitor. In another aspect, the cathepsin inhibitor is epoxisuccinate and derivative thereof; E-64; E-64a; E-64b; E-64c; E-64d; CA-074; CA-074 Me; CA-030; CA-028; peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac-LVK-CHO, Z-Phe-Tyr-CHO, Z-Phe- Tyr(0tBu)-C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp- CHO, Z- Phe-Leu-C0CH0.H20; peptidyl semicarbazone derivatives; peptidyl methylketone derivatives; peptidyl trifluoromethylketone derivatives Biotin- Phe-Ala-fluoromethyl ketone, Z-Leu-Leu- Leu-fluoromethyl ketone, Z-Phe-Phe-fluoromethyl ketone, N-Methoxysuccinyl-Phe-HOMO- Phe-fluoromethyl ketone, Z-Leu-Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone; peptidylchloromethases and derivatives thereof; peptidylhydroxymates and derivatives thereof; peptidylhydroxylamines and derivatives thereof; peptidyl acyloxymethanes and derivatives thereof; peptidylacyloxymethyl ketones and derivatives thereof; peptidyl aziridines and derivatives thereof; peptidyl aryl vinyl sulfones and derivatives thereof; peptidyl arylvinylsulfonates and derivatives thereof; gallinamide analogs and derivates thereof; peptidyl aldehydes and derivatives thereof; azepinone-based inhibitors and derivatives thereof; nitrile- containing inhibitors and derivates thereof; thiosemicarbazone and derivatives thereof; propeptide mimics and derivatives thereof; thiocarbazate, oxocarbazate, azapaptides and derivatives thereof; peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ-Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala-CHN2, Z-Phe-Thr(OBzl)- CHN2, Z-Phe-Tyr (Ot- But)-CHN2, Z-Leu-Leu-Tyr-CHN2; peptidyl acyloxymethyl ketones; peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS; peptidyl nitriles; peptidyl disulfides, 5,5'-dithiobis[2- nitrobenzoic acid], cysteamines, 2,2'-dipyridyl disulfide; non- covalent inhibitors, N-(4- Biphenyl acetyl)-S-methyl cysteine-(D)-Arg-Phe-b-phenethylamide; thiol alkylating agents, maleimides, etc; azapeptides; azobenzenes; O-acylhydroxamates, Z-Phe- Gly-NHO-Bz, Z-FG-NHO-BzOME; lysosomotropic agents, chloroquine, ammonium chloride; Cystatin A, Cystatin B, Cystatin C, Cystatin D, Cystatin F, stefins, kininogens, Sialostain L, antimicrobial peptide LL- 37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50; Odanacatib (MK-0822), Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), SLV213 (K777 or K1777), RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV- 701, MIV-710, MIV-711, NC-2300, ORG-219517, ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY- 106; VBY-285;VBY- 825), VBY- 129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV32247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI- 1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY- 210953), AL101 (BMS906024), BMS-986115 5 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP- 0015962), SAR-164653, KGP94, VEL-0230, and BLD2660. [0077] Other cathepsin inhibitors are described in Dana et al., 2020. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 1025: 698, incorporated herein by reference thereto and may be useful in the present disclosure.
Additional Therapeutic Agents
[0078] In some embodiments, the drug combinations of the disclosure may be combined with other therapeutic agents.
[0079] In some such embodiments, the drug combinations of the disclosure may be combined with or include other therapeutic modality e.g., radiotherapy or plasmapheresis or another therapeutic agent.
[0080] The drug combinations of the present disclosure can be used together with additional therapeutic agents for the prophylaxis or treatment of various diseases. For example, when the drug combination of the present disclosure is used as an antiviral therapy, it can be used together with the any of the drugs described herein.
Non-steroidal anti-inflammatory drugs (NSAlDs)
[0081] In some embodiments, compositions of the disclosure may include NSAIDs.
[0082] In some aspects, the NSAIDs may be classical NSAIDs, such as, but not limited to, alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lomoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium aurothiomalate, hyaluronate sodium, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof and the like.
[0083] In some aspects, the NSAIDs may be cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2 selective inhibitor and the like) salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen and the like.
[0084] In some aspects, the NSAIDs may be nitric oxide-releasing NSAIDs. Disease-modifying anti-rheumatic drugs (DMARDs)
[0085] In some embodiments, formulations may include gold preparations. As used herein, the term gold preparations may include auranofin. In some embodiments, formulations may include penicillamine, which may include D-penicillamine. In some embodiments, formulations may include aminosalicylic acid preparations, which may include sulfasalazine, mesalazine, olsalazine, balsalazide. In some embodiments, formulations may include antimalarials, which may include chloroquine. In some embodiments, formulations may include pyrimidine synthesis inhibitors, which may include leflunomide. In some embodiments, formulations may include prograf.
Anti-cytokine drug
[0086] In some embodiments, formulations may include protein drugs. As used herein, protein drugs may include TNF inhibitors such as etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-alpha, soluble TNF-alpha receptor, TNF-alpha binding protein, anti-TNF-alpha antibody. As used herein, protein drugs may include interleukin- 1 inhibitors, such as anakinra (interleukin- 1 receptor antagonist), soluble interleukin- 1 receptor and the like; interleukin-6 inhibitors such as tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody. As used herein, protein drugs may include interleukin- 10 drugs such as interleukin- 10. As used herein, protein drugs may include interleukin- 12/23 inhibitors such as ustekinumab, briakinumab (anti-interleukin- 12/23 antibody). As used herein, protein drugs may include B cell activation inhibitors such as rituximab, belimumab and the like; co-stimulatory molecules-related protein preparations such as abatacept and the like; complement mediated inhibitors both synthetic and biologic.
[0087] In some embodiments, formulations may include non-protein drugs such as MAPK inhibitors such as BMS-582949. As used herein, non-protein drugs may include gene modulators; inhibitors of molecule involved in signal transduction, such as NF-kappa, NF-kappaB, IKK-1, IKK-2, AP- 1. As used herein, non-protein drugs may include cytokine and chemokine production inhibitors, receptor binding inhibitors such as iguratimod, tetomilast. As used herein, non-protein drugs may include TNF-alpha converting enzyme inhibitors; interleukin- 1 beta converting enzyme inhibitors such as VX-765. As used herein, non-protein drugs may include interleukin-6 antagonists such as HMPL-004. As used herein, non-protein drugs may include interleukin-8 inhibitors such as IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin. As used herein, non protein drugs may include Chemokine antagonists such as CCR9 antagonist (CCX-282, CCX- 025), MCP-1 antagonist. As used herein, non-protein drugs may include interleukin-2 receptor antagonists such as denileukin, diftitox. As used herein, non-protein drugs may include therapeutic vaccines such as TNF-alpha vaccine. As used herein, non-protein drugs may include gene therapy drugs such as drugs promoting the expression of a gene having an anti inflammatory action such as interleukin-4, interleukin- 10, soluble interleukin- 1 receptor, soluble TNF-alpha receptor. As used herein, non-protein drugs may include antisense compounds such as ISIS-104838.
Integrin inhibitor
[0088] In some embodiments, formulations may include integrin inhibitors such as natalizumab, vedolizumab, AJM300, TRK-170, and/or E-600.
Immunomodulator (immunosuppressant)
[0089] In some embodiments, formulations may include immunomodulators such as cyclophosphamide, MX-68, atiprimod dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, intravenous immunoglobulin, anti-thymocyte globulin, and/or RSLV-132.
Proteasome inhibitor
[0090] In some embodiments, formulations may include proteasome inhibitors such as bortezomib.
JAK inhibitor
[0091] In some embodiments, formulations may include JAK inhibitors such as tofacitinib. Steroids
[0092] In some embodiments, formulations may include steroids. As used herein, steroid may include dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone dipropionate, and/or estriol. Angiotensin converting enzyme inhibitors
[0093] In some embodiments, formulations may include angiotensin converting enzyme inhibitors. As used herein, angiotensin converting enzyme inhibitors may include enalapril, captopril, ramipril, lisinopril, cilazapril, and/or perindopril.
Angiotensin II receptor antagonists
[0094] In some embodiments, formulations may include angiotensin II receptor antagonists. As used herein, angiotensin II receptor antagonists may include candesartan, candesartan cilexetil (TCV-116), valsartan, irbesartan, olmesartan, and/or eprosartan. Siuretic substances
[0095] In some embodiments, formulations may include a diuretic. As used herein, a diuretic may include hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, and/or cyclopenthiazide.
Cardiotonic substances
[0096] In some embodiments, formulations may include a cardiotonic substance. As used herein, a cardiotonic substance may include digoxin, and/or dobutamine.
Beta receptor antagonists
In some embodiments, formulations may include a beta receptor antagonist. As used herein, a beta receptor antagonist may include carvedilol, metoprolol, and/or atenolol.
Ca sensitizers
[0097] In some embodiments, formulations may include a Ca sensitizer. As used herein, a CA sensitizer may include MCC-135.
Ca channel antagonists
[0098] In some embodiments, formulations may include Ca channel antagonists. As used herein, a Ca channel antagonist may include nifedipine, diltiazem, and/or verapamil.
Anti-platelet drug, anticoagulator
[0099] In some embodiments, formulations may include an anti-platelet substance or anticoagulator. As used herein, an anti-platelet substance or anticoagulator may include heparin, aspirin, and/or warfarin.
HMG-CoA reductase inhibitors
[0100] In some embodiments, formulations may include an anti-platelet substance or anticoagulator. As used herein, an anti-platelet substance or anticoagulator may include atorvastatin, and/or simvastatin.
Other substances
[0101] In some embodiments, formulations may include other substances which improve functionality of the compound. As used herein, other substances may include T cell inhibitors, inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolate mofetil. As used herein, other substances may include adhesion molecule inhibitor such as ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1. As used herein, other substances may include thalidomide, a combination of cathepsin inhibitor or a single cathepsin inhibitor, matrix metalloprotease (MMPs) inhibitor such as V-85546. As used herein, other substances may include glucose-6-phosphate dehydrogenase inhibitor, Dihydroorotate dehydrogenase (DHODH) inhibitor, phosphodiesterase IV (PDE IV) inhibitor such as roflumilast, CG-1088. As used herein, other substances may include a phospholipase A2 inhibitor, iNOS inhibitor such as VAS-203. As used herein, other substances may include microtubule stimulating compound such as paclitaxel. As used herein, other substances may include microtubule inhibitor such as reumacon. As used herein, other substances may include MHC class II antagonist, prostacyclin agonist such as iloprost. As used herein, other substances may include CD4 antagonist such as zanolimumab. As used herein, other substances may include CD23 antagonist, LTB4 receptor antagonist such as DW-1305. As used herein, other substances may include 5 -lipoxygenase inhibitor such as zileuton. As used herein, other substances may include cholinesterase inhibitor such as galanthamine. As used herein, other substances may include a tyrosine kinase inhibitor such as Tyk2 inhibitor (WO 2010/142752). As used herein, other substances may include cathepsin B inhibitor. As used herein, other substances may include adenosine deaminase inhibitor such as pentostatin. As used herein, other substances may include osteogenesis stimulator, dipeptidylpeptidase inhibitor, collagen agonist, capsaicin cream, hyaluronic acid derivative synvisc (hylan G-F 20), orthovis. As used herein, other substances may include glucosamine sulfate, amiprilose. As used herein, other substances may include CD-20 inhibitors such as rituximab, ibritumomab, tositumomab, ofatumumab. As used herein, other substances may include BAFF inhibitors such as belimumab, tabalumab, atacicept, A-623. As used herein, other substances may include CD52 inhibitors such as alemtuzuma.
[0102] In some embodiments, formulations may include other substances which improve functionality of the compound. As used herein, other substances may include antiviral substances such as idoxuridine, acyclovir, vidarabine, gancyclovir. As used herein, other substances may include anti-HIV agents such as zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, and/or ritonavir.
Combinations
[0103] The drug combinations of the disclosure can be combined with other therapeutic agents. Drug combinations of the disclosure can include, but are not limited to, for example, Relacatib (GSK-462795, SB-462795) in combination with PF-07321332, PF-07304814, or PF- 00835231 for use in treatment of pathogenic CoV such as SARS-CoV. Relacatib (GSK-462795, SB-462795) in combination with AT-527 or AT-511 for use in treatment of pathogenic CoVs such as SARS-CoVs. SFV-213, K777, or K-1777 in combination with AT-527 or AT-511 for use in pathogenic CoVs such as SARS CoVs. SFV-213, K777, or K-1777 in combination with PF- 07321332, PF-07304814, or PF-00835231 for use in treatment of pathogenic CoVs such as SARS-CoVs. SFV-213, K777, or K-1777 in combination with T-705, GS-5734 (remdesivir) for treatment of pathogenic CoVs such as SARS-CoVs. Relacatib (GSK-462795, SB-462795), in combination with T-705 (Avigan) for use in the treatment of arenavirus infections; Relacatib (GSK-462795, SB-462795), in combination with T-705 (Avigan) for use in the treatment of SARS-CoV-2 infections; MIV-711, in combination with T-705 (Favipiravir, Avigan) for use in treatment of SARS CoV-2 and other coronaviruses such as MERS and SARSCoV; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB- 462795), in combination with JNJ-64041575, JNJ-1575, ALS-008176, AL-8176 (Lumicitabine) for use in the treatment of RSV infections; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB-462795), in combination with JNJ-64041575, JNJ- 1575, ALS-008176, AL-8176 (Lumicitabine) for use in the treatment of SARS-CoV-2 infections; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB-462795) or Odanacatib (MK-0822) or Balicatib (AAE581), in combination with JNJ- 64041575, JNJ-1575, ALS-008176, AL-8176 (Lumicitabine) for use in the treatment of RSV infections; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB-462795) in combination with T-705 (Avigan, Favipiravir) or BCX 4430 (Galidesivir) for use in the treatment of SARSCoV- 2 infections; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB-462795), in combination with GS-5734 (Redmdesivir) in the treatment of SARS-CoV-2 infections; Odanacatib (MK-0822) or Balicatib (AAE581), in combination with GS-5734 (Redmdesivir) in the treatment of SARS- CoV-2 infections; Relacatib (GSK-462795, SB-462795), in combination with T-705 (Avigan, Favipiravir) along with lopinavir/ritonavir (Kaletra) for use in the treatment of filovirus infections; Relacatib (GSK-462795, SB-462795), in combination with T-705 (Avigan), along with lopinavir/ritonavir (Kaletra) for use in the treatment of coronavirus infections such as SARSCoV- 2 infections; Relacatib (GSK-462795, SB-462795), in combination with T-705 (Avigan), along with lopinavir/ritonavir (Kaletra) for use in the treatment of coronavirus infections such as SARS- CoV-2 and other coronaviruses such as MERS and SARSCoV; AM- 3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB- 462795), in combination with JNJ-64041575, JNJ-1575, ALS-008176, AL-8176 (Lumicitabine) for use in the treatment of RSV infections; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB-462795), in combination with BCX4430 (Galidesivir), T-705 (Avigan, Favipiravir) along with a mammalian protease inhibitor such as darunavir (Prezista) in the treatment of coronavirus infections such as SARSCoV- 2 infections; AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517 or Relacatib (GSK-462795, SB-462795), in combination with GS-5734 (Remdesivir), along with a mammalian protease inhibitor such as darunavir (Prezista) in the treatment of coronavirus infections such as SARS- CoV-2 infections; Odanacatib (MK-0822) or Balicatib (AAE581), in combination with GS-5734 (Remdesivir), along with a mammalian protease inhibitor such as darunavir (Prezista) in the treatment of coronavirus infections such as SARS-CoV-2 and other pathogenic CoVs infections. Antiviral antibodies in combination with direct antiviral such as AT-527 and/or cathepsin inhibitors such as Balicatib, SLV-213.
[0104] In some embodiments, the combination or mixture of the present disclosure or a formulation thereof is administered in conjunction with the other therapeutic modality. In certain such embodiments, the other therapeutic modality is one that is normally administered to patients with the disease to be treated or prevented.
Ill FORMULATIONS
[0105] In some embodiments, a pharmaceutically acceptable salt of the combination or mixture of the disclosure may be utilized. If a pharmaceutically acceptable salt of the combination or mixture of the disclosure or a citric acid ester thereof is utilized in these compositions, the salt preferably is derived from an inorganic or organic acid or base. For examples of suitable salts, see, e.g., Berge et al, J. Pharm. Sci. 66: 1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams &
Wilkins, 2000.
[0106] Non-limiting examples of suitable acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalene sulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
[0107] Suitable base addition salts include, without limitation, ammonium salts, alkali metal salts, such as lithium, sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; other multivalent metal salts, such as zinc salts; salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, t butylamine, ethylene diamine, ethanolamine, and choline; and salts with amino acids such as arginine, lysine, and so forth.
[0108] The formulation comprises the combination, whether as separate compounds or as a mixture, of the present disclosure and a pharmaceutically acceptable carrier.
[0109] The term “pharmaceutically acceptable carrier” is used herein to refer to a material that is compatible with a recipient subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent. The toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent. The terms “carrier”, “adjuvant”, or “vehicle” are used interchangeably herein, and include any and all solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, pH modifiers, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compound of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, carbonates, magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, pyrogen-free water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose, sucrose, and mannitol, starches such as com starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth; malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil, glycols such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, alginic acid, isotonic saline, Ringer's solution, alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, and glycerol, cyclodextrins such as hydroxypropyl beta-cyclodextrin and sulfobutylether beta-cyclodextrin, lubricants such as sodium lauryl sulfate and magnesium stearate, petroleum hydrocarbons such as mineral oil and petrolatum. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [0110] While it is possible for the active ingredients of the combination to be administered alone and separately as monotherapies, it is preferable to administer them as a pharmaceutical co formulation. A two-part or three-part combination may be administered simultaneously or sequentially. When administered sequentially, the combination may be administered in one, two, or three administrations. Preferably, two-part or three-part combinations are administered in a single pharmaceutical dosage form. More preferably, a two-part combination is administered as a single oral dosage form and a three-part combination is administered as two identical oral dosage forms.
[0111] It will be appreciated that the compounds of the combination may be administered: (1) simultaneously by combination of the compounds in a co-formulation or (2) by alternation, i.e. delivering the compounds serially, sequentially, in parallel or simultaneously in separate pharmaceutical formulations.
[0112] In alternation therapy, the delay in administering the second, and optionally a third active ingredient, should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. By either method of administration (1) or (2), ideally the combination should be administered to achieve peak plasma concentrations of each of the active ingredients. A one pill once-per-day regimen by administration of a combination co formulation may be feasible for some IV-positive patients. Effective peak plasma concentrations of the active ingredients of the combination will be in the range of approximately 0.001 pM to 10 mM. Optimal peak plasma concentrations may be achieved by a formulation and dosing regimen prescribed for a particular patient. It will also be understood that either active ingredient, or the physiologically functional derivatives of either thereof, whether presented simultaneously or sequentially, may be administered individually, in multiples, or in any combination thereof. In general, during alternation therapy, an effective dosage of each compound is administered serially, where in co-formulation therapy , effective dosages of two or more compounds are administered together.
[0113] When the individual components of the combination are administered separately they are generally each presented as a pharmaceutical formulation. The references hereinafter to formulations refer unless otherwise stated to formulations containing either the combination or a component compound thereof. It will be understood that the administration of the combination of the disclosure by means of a single patient pack, or patient packs of each formulation, within a package insert diverting the patient to the correct use of the disclosure is a desirable additional feature of this disclosure . The disclosure also includes a double pack comprising in association for separate administration, formulations of the drug and protease, or a physiologically functional derivative of either or both thereof. The combination therapies of the disclosure include: (1) a combination of drug and mammalian protease inhibitor or (2) a combination containing a physiologically functional derivative of either or both thereof.
[0114] The combination may be formulated in a unit dosage formulation comprising a fixed amount of each active pharmaceutical ingredient for a periodic, e.g. daily, dose or sub-dose of the active ingredients. Pharmaceutical formulations according to the present disclosure comprise a combination according to the disclosure together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
[0115] Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared (Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).
[0116] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of formulations and such compositions may contain one or more agents including antioxidants, sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example pregelatinized starch, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
[0117] Aqueous suspensions of the disclosure contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth 5 and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). [0118] The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, sucralose or saccharin. Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid, BHT, etc. Dispersible powders and granules of the disclosure suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[0119] The formulations of the disclosure may also be in the form of oil in- water emulsions or liposome formulations. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
[0120] The formulations of the disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 -butane diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
[0121] The formulations of the disclosure may be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
[0122] The formulations of the disclosure may also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container or a nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1, 1,2-tetrafluoroethane (HFC 134a), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the composition, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
[0123] Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a formulations of the disclosure and a suitable powder base such as lactose or starch. Aerosol or dry powder formulations are preferably arranged so that each metered dose or “puff contains from 20 pg to 200 mg of a composition for delivery to the patient. The overall daily dose with an aerosol or nebulizer will be in the range of from 20 pg to 200 mg which may be administered in a single dose or, more usually, in divided doses throughout the day. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight: weight).
[0124] The formulations can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from 5 about 3 to 500 pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 milJhr can occur.
[0125] As noted above, formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
[0126] The combinations of the disclosure may conveniently be presented as a pharmaceutical formulation in a unitary dosage form. A convenient unitary dosage formulation contains the active ingredients in any amount from 1 mg to 1 g each, for example but not limited to, 10 mg to 300 mg. The synergistic effects of a drug in combination with a mammalian protease inhibitor may be realized over a wide ratio, for example 1 : 1,000 to 1,000: 1 (drug: mammalian protease inhibitor). In one embodiment, the ratio may range from about 1: 10 to 10: 1. In another embodiment, the weight/weight or concentration/concentration ratio of drug to mammalian protease inhibitor in a co-formulated combination dosage form, such as a pill, tablet, caplet or capsule will be about 1, i.e. an approximately equal amount of drug and mammalian protease inhibitor. In other exemplary co-formulations, there may be more or less drug than mammalian protease inhibitor. For example, 300 mg drug and 200 mg mammalian protease inhibitor can be co formulated in a ratio of 1.5: 1 (drug: mammalian protease inhibitor). In one embodiment, each compound will be employed in the combination in an amount at which it exhibits antiviral activity when used alone. Other ratios and amounts of the compounds of said combinations are contemplated within the scope of the disclosure .
[0127] It will be appreciated by those skilled in the art that the amount of active ingredients in the combinations of the disclosure required for use in treatment will vary according to a variety of factors, including the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or health care practitioner. The factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated. [0128] It is also possible to combine any two of the active ingredients in a unitary dosage form for simultaneous or sequential administration with a third active ingredient. The three-part combination may be administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or three administrations. Third active ingredients may have drug enhancing activity, similar activity as the drug, for example having anti-viral activity and include protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI). and integrase 5 inhibitors, or additional protease inhibitors. Exemplary third active ingredients to be administered in combination with drug and protease inhibitor, and their physiological functional derivatives, are 5,6 dihydro-5 -azacytidine 5-aza 2'deoxycytidine 5-azacytidine 5 5-yl-carbocyclic 2'- deoxyguanosine (BMS200,475) 9 (arabinofuranosyl)guanine; 9-(2' deoxyribofuranosyl)guanine 9-(2'-deoxy 2 'fluororibofuranosyl)-2,6-diaminopurine 9-(2'-deoxy 2'fluororibofuranosyl)guanine 9-(2'- deoxyribofuranosyl)-2,6 diaminopurine 9- (arabinofuranosyl)-2,6 diaminopurine Abacavir, Ziagen® Acyclovir, ACV; 9-(2- hydroxyethoxylinethyl)guanine Adefovir dipivoxil, Hepsera® amdoxivir, DAPD 15 Aniprenavir, Agenerase® araA; 9-0-D-arabinofuranosyladenine (Vidarabine) atazanivir sulfate (Reyataz®) AZT; 3'-azido-2',3'- dideoxythymidine, Zidovudine, (Retrovir®) BHCG; (.-i- .)-(l a, 2 b, 3 a)-9-[2,3- bis(hydroxymethyl)cyclobutyl]guanine BMS200,475; 5-yl-carbocyclic 2'-deoxyguanosine Buciclovir;, (R) 9-(3,4- dihydroxybutyl)guanine BvaraU; l-]l-Darabinofuranosyl- E-5-(2-bromovinyl)uracil (Sorivudine) Calanolide A Capravirine CDG; carbocyclic 2'-deoxyguanosine Cidofovir, HPMI'C; (S)- 9 -(3- hydroxy-2- phosphonyhnethoxypropyl)cytosine Clevudine, L-FMAU; 2 '-Fluoro-5-methyl4— arabino-furanosyluracil Combivir® (lamivudine/zidovudine) Cytallene; [ 1 -(4'- hydroxy- 1 ',2'- butadienyl)cytosine] 30 d4C; 3'- deoxy-2',3'-didehydrocytidine DAPD; (-)-l-D-2,6- diaminopurine dioxolane ddA; 2',3'-dideoxyadenosine ddAPR; 2,6-diaminopurine-2',3'- dideoxyriboside ddC; 2',3'-dideoxycytidine (Zalcitabine) ddl; 2', 3'- 5 dideoxyinosine, didanosine, (Videx®, Videx® EC) Delavirdine, Rescriptor® Didanosine, ddl, Videx®; 2',3'-dideoxyinosine DXG; dioxolane guanosine E-5- (2-bromovinyl)-2'-deoxyuridine Efavirenz, Sustiva®D Enfuvirtide, Fuzeon® F-ara-A; fluoroarabinosyladenosine (Fludarabine) FDOC; (-)-l- D-5- fluoro- l-12-(hydroxymethyl)-l ,3- dioxolane]cytosine FEAU; 2'-deoxy-2'-fluoro— p3- Darabinofuranosy- 5-ethyluraciI FIAC; 1 -(2-deoxy-2- fluoro-p3-D-arabinofuranosyl)-5- iodocytosine 15 FIAU; l-(2-deoxy-2-fluoro-p3-D-arabinofuranosyl)-5- iodouridine FFG; 2', 3'- dideoxy-3'-fluoroguanosine FFT; 3'-deoxy-3'-fluorothymuidine Fludarabine; Fara- A; fluoroarabinosyladenosine FMAU; 2'-Fluoro-5- methyl -fp-F-arabino-furanosyluracil FMdC Foscamet; phosphonoformic acid, PFA FPMPA; 9-(3- fluoro-2- phosphonylmethoxypropyl)adenine Gancyclovir, GCV; 9-(l,3-dihydroxy-2- propoxymethyl)guanine GS-7340; 9-[R-24[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyllmethoxy]propyl adenine HPA; (S)- 9-(3 -hydroxy-2 - phosphonylmethoxypropyl)adenine HPMPC; (S)-9-(3-hydroxy-2- phosphonylmeffioxypropyl)cytosine (Cidofovir) Hydroxyurea, Droxia® Indinavir, Crixivan®, Kaletra® (lopinavir/ritonavir) Lamnivudine, 3TC, Epivi T m ; (2R, 5S, cis)-4-amino-l-(2- hyclroxymethyl-1,3 oxathiolan-5-yl)-(lH)-pyiidin-2- one L-d4C; L-3'-dcoxy-2',3'- didehydrocytidine L-ddC; L-2',3'-dideoxycytidine 5 L-Fd4C; L-3'-deoxy-2',3'- didehydro-5- fluorocytidine L-FddC; F-2',3'-dideoxy 5-fluorocytidine Fopinavir Nelfmavir, Viracept® Nevirapine, Viramune® Oxetanocin A; 9-(2-deoxy-2-hydroxymethy-3-D-erythro- oxetanosyl)adenine Oxetanocin G; 9-(2-deoxy-2-hydroxymethy-3-D- 5 erythroxetanosyl)guanine Penciclovir PMEBDAP; 9-(2-phosphonylinethoxyethyl)-2,6-diaminopurine PMPA, tenofovir; (R)-9-(2-phosphonylmethoxypropyl)adenine PPA; phosphonoacetic acid Ribavirin; 1-1- Dribofuranosyl-,2,4-triazole-3-carboxamide Ritonavir, Norvir® Saquinavir, Invirase®, Fortovase® Sonivudine, BvaraU; l-J0-D-arabinofuranosyl-E-5-(2- bromovinyl)uracil Stavudine, d4T, Zerit®; 2',3'-didehydro-3'-deoxythyinidine Trifluorothymidine, TFT; Trifluorothyinidine Trizivir® (abacavir sulfate/lamivudine/zidovudine) Vidarabine, araA; 9-1-D- arabinofuranosyladenine Zalcitabine, Hlivid®,ddC; 2',3'-dideoxycytidine 25 Zidovudine, AZT, Retrovir®; 3-azido-2',3'-dideoxythymdine Zonavir; 5-propynyl-l-arabinosyluracil. Another aspect of the present disclosure is a three-part combination comprising tenofovir DF, FTC, and 9- [(R)-2-[[(S)-[[(S) l(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]me thoxy] propyl] adenine, also designated herein as GS-7340, GS-5734 (Remdesivir), Al-8170, and JNJ- 64041575, JNJ-1575, AFS-008176, Al-8176 (Fumicitabine).
[0129] A further aspect of the disclosure is a patient pack comprising at least one active ingredient: drug, mammalian protease inhibitor, or a physiologically functional derivative of either of the combination and an information package or product insert containing directions on the use of the combination of the disclosure . Segregation of active ingredients in pharmaceutical powders and granulations is a widely recognized problem that can result in inconsistent dispersions of the active ingredients in final dosage forms. Some of the main factors contributing to segregation are particle size, shape and density. Segregation is particularly troublesome when attempting to formulate a single homogenous tablet containing multiple active ingredients having different densities and different particle sizes. Glidants are substances that have traditionally been used to improve the flow characteristics of granulations and powders by reducing interparticulate friction. See Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1, p. 177-178 (1989), incorporated herein by reference.
[0130] Glidants are typically added to formulations immediately prior to tablet compression to facilitate the flow of granular material into the die cavities of tablet presses. Glidants include: colloidal silicon dioxide, asbestos free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, com starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, and magnesium oxide. Glidants can be used to increase and aid blend composition homogeneity in formulations of drugs (US Patent No. 6113920). The novel compositions of the present disclosure may contain glidants to effect and maintain homogeneity of active ingredients during handling prior to tablet compression. [0131] The present disclosure provides pharmaceutical formulations combining the active ingredients, a drug, a mammalian protease inhibitor, or physiologically functional derivatives thereof, in a sufficiently homogenized form, and a method for using this pharmaceutical formulation. An object of the present disclosure is to utilize glidants to reduce the segregation of active ingredients in pharmaceutical compositions during pre-compression material handling. Another object of the present disclosure is to provide a pharmaceutical formulation combining the active ingredients drug and mammalian protease inhibitor, or physiologically functional derivatives thereof, with a pharmaceutically acceptable glidant, resulting in a mixture characterized by a pharmaceutically acceptable measure of homogeneity. Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present disclosure and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients, and maintaining chemical stability.
[0132] In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross linked povidone, cross- linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, cellulose ether derivatives (e.g., hydroxypropyl methylcellulose) or methacrylate derivatives in varying proportions to provide the desired release profde. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0133] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylates. Topical administration may also be by means of a transdermal iontophoretic device. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Formulations suitable for penile administration for prophylactic or therapeutic use may be presented in condoms, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds. Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti -oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[0134] Exemplary unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this disclosure may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents. The compounds of the combination of the present disclosure may be obtained in a conventional manner, known to those skilled in the art.
IV. DOSING AND ADMINISTRATION
[0135] Compositions of the present disclosure may be administered to a human or other mammal in a safe and effective amount as described herein. These safe and effective amounts will vary according to the type and size of mammal being treated and the desired results of the treatment. Any of the various methods known by persons skilled in the art for packaging tablets, caplets, or other solid dosage forms suitable for oral administration, that will not degrade the components of the present disclosure, are suitable for use in packaging. The combinations may be packaged in glass and plastic bottles. Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials optionally including a desiccant, e.g. silica gel. Packaging may be in the form of unit dose blister packaging. For example, a package may contain one blister tray of drug and another blister tray of protease pills, tablets, caplets, or capsule. A patient would take one dose, e.g. a pill, from one tray and one from the other. Alternatively, the package may contain a blister tray of the co-formulated combination of drug and protease in a single pill, tablet, caplet or capsule. As in other combinations and packaging thereof, the combinations of the disclosure include physiological functional derivatives of drug and protease. The packaging material may also have labeling and information related to the formulation printed thereon.
[0136] For any compound described herein the therapeutically effective amount can be initially determined from preliminary in vitro studies and/or animal models. A therapeutically effective dose can also be determined from human data for inhibitors which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. For instance, many cathepsin inhibitors have been extensively studied. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
[0137] The drug combination and other therapeutic agent may be administered simultaneously or sequentially. When the other therapeutic agents are administered simultaneously they can be administered in the same or separate formulation, but are administered at the same time. The other therapeutic agents are administered sequentially with one another and with the drug combination, when the administration of the other therapeutic agents and the drug combination is temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer. Other therapeutic agents include but are not limited to anti-viral vaccines and anti -viral agents. In some instances, the drug combination is administered with multiple therapeutic agents, i.e., 2, 3, 4 or even more different therapeutic agents.
[0138] In the above embodiments, the other therapeutic agent may be administered in the same dosage form or as a separate dosage form. When administered as a separate dosage form, the other therapeutic agent may be administered prior to, at the same time as, or following administration of the compound of the present disclosure or a formulation thereof.
[0139] While the dose varies depending on the target disease, symptom, subject of administration, administration method and the like, for oral administration as a therapeutic agent, for example, it is generally about 001-100 mg/kg body weight, preferably 005-30 mg/kg body weight, more preferably 05-10 mg/kg body weight, as one dose of the compound of the present disclosure , which is, for example, administered once to 3 times a day, on a weekly schedule, on a twice-weekly schedule and the like.
[0140] In some embodiments, the combination or mixture of the present disclosure or a formulation thereof is administered on a weekly schedule. In some embodiments, the drug or mammalian protease inhibitor, for example a cathepsin inhibitor, or a formulation thereof is administered on a weekly schedule. In some embodiments, the combination or mixture of the present disclosure or a pharmaceutical composition thereof is administered on days 1, 8, and 15 of a 28-day cycle. In some embodiments, the drug or mammalian protease inhibitor, for example a cathepsin inhibitor, or a formulation thereof is administered on days 1, 8, and 15 of a 28-day cycle. [0141] In some embodiments, the combination or mixture of the present disclosure or a pharmaceutical composition thereof is administered on a twice weekly schedule. In some embodiments, the drug or the mammalian protease inhibitor, for example a cathepsin inhibitor, or a formulation thereof is administered on a twice-weekly schedule.
[0142] In some embodiments, the combination or mixture of the present disclosure or a formulation thereof is administered on days 1, 4, 8, and 11 of a 21 -day cycle. In some embodiments, the drug or the mammalian protease inhibitor, for example a cathepsin inhibitor, or a formulation thereof is administered on days 1, 4, 8, and 11 of a 21 -day cycle.
[0143] Additionally, an article of manufacture may contain a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a “package insert.” A package insert may be attached to or included with a pharmaceutical article of manufacture. The package insert and any article of manufacture labeling provides information relating to the formulations. The information and labeling provides various forms of information utilized by health-care professionals and patients, describing the composition, its dosage and various other parameters required by regulatory agencies such as the United States Food and Drug Administration and other drug regulatory bodies such as EMA (European Medical Authorities).
V. METHODS OF USE
[0144] The present disclosure provides methods of use of compositions of the disclosure in a subject. The methods may include methods for improving drug efficacy, drug toxicity and/or lowering drug dose in a subject.
[0145] In some embodiments, the present disclosure provides methods for improving the efficacy of a drug by combining the drug with one or more mammalian protease inhibitors. Such combinations may increase function or efficacy of the drug, by about 2% and above, or between about 2%- 5%, about 5%-10%, about 10%-20%, about 20%-30%, 10 about 30%-40%, about 40%-50%, about 50%-60%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%- 100%, about 100%- 150%, about 150%-200%, about 200%- 300%, about 300%-400%, about 400%-500%, about 500%- 1000%, 1000%-5000%, about 5000%-7000%, about 7000%- 10,000% or more, or about 0.001-fold to about 0.01 fold, about 0.05-fold to about 0.1-fold, about 0.1- fold to about 0.5-fold, about 0.5-fold to about 1- fold, about 1-fold to about 2-fold, about 3- fold to about 5 -fold, about 5 -fold to about 10-fold, about 10-fold to about 20-fold, about 20-fold to about 40- fold, about 50-fold to about 75-fold, about 80 fold to about 100-fold, or more, such that the effective dose is decreased for each drug mentioned in this disclosure. As used herein, effective dose may refer to the is that that achieves 50% of the effect (also termed Inhibitory Concentration 50% (IC50) or Effective Concentration (EC50)) in assays in vitro, wherein the EC50 is decreased by about 5% or more, or by about 5%-10%, about 10%-20%, about 20%-30%, about 30%-40%, about 3040%-50%, about 50%-60%, about 60%-70%, about 70%- 80%, about 80%-90%, about 90%-100%, about 100%-150%, about 150%-200%, about 200%-300%, about 300%-400%, about 400%-500%, about 500%-1000%, 1000%-5000%, about 5000%-7000%, about 7000%-10,000% or more. “Sub-optimal doses” may refer to doses which do not reach EC50 or IC50.
[0146] In some embodiments, the present disclosure provides methods for reducing the toxicity of a drug by combining the drug with one or more mammalian protease inhibitors. Such combinations may reduce the toxicity of the drug, by about 2% and above, or between about 2%- 5%, about 5%-10%, about 10%-20%, about 20%-30%, 10 about 30%-40%, about 40%-50%, about 50%-60%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%- 100%, about 100%- 150%, about 150%-200%, about 200%- 300%, about 300%-400%, about 400%-500%, about 500%- 1000%, 1000%-5000%, about 5000%-7000%, about 7000%- 10,000% or more, or about 0.001-fold to about 0.01 fold, about 0.05-fold to about 0.1-fold, about 0.1- fold to about 0.5-fold, about 0.5-fold to about 1- fold, about 1-fold to about 2-fold, about 3-fold to about 5- fold, about 5 -fold to about 10-fold, about 10-fold to about 20-fold, about 20-fold to about 40- fold, about 50-fold to about 75-fold, about 80 fold to about 100-fold, or more, such that the toxicity is decreased for each drug mentioned in this disclosure.
[0147] In one embodiment of the disclosure , the subject or patient has or is at risk of infection by a virus, such as RNA or DNA viruses which are pathogenic to humans and animals. In another embodiment of the disclosure , the subject has or is at risk of infection by a Type I enveloped virus. In some embodiments, the compositions of the disclosure may be provided or administered to a subject with an infection associated with a Type I enveloped virus e.g. a filovirus. In still another embodiment, the compositions may be used in the treatment of or may be provided to a subject infected with a fdo virus such as an Ebola virus or a Marburg virus. In yet another embodiment, the compositions may be used in the treatment of or may be provided to a subject infected with a Type I enveloped virus such as an orthomyxovirus. In still another embodiment, the compositions may be used in the treatment of or may be provided to a subject infected with a Type I enveloped virus such as a paramyxovirus. In still another embodiment, the Type I enveloped virus is an Arenavirus.
[0148] In another embodiment of the disclosure , the subject has or is at risk of infection by a virus such as, but not limited to, coronaviruses, filoviruses, flaviviruses such as hepatitis-C virus, bunyaviruses, poxvirus, arboroviruses such as Togaviruses, bunyaviruses, orthomyxoviridae, paramyxoviridae, poxviruses, herpesviruses, henipaviruses, hepadnaviruses, rhabdoviruses, bomaviruses, arteriviruses, papillomaviridae, human retroviruses, polyomaviridae, picomaviridae, , and adenoviridae.
[0149] In some embodiments, the disclosure provides for methods of treating infection by a virus of the family Filoviridae, a family of viruses with a single-stranded, unsegmented (-) sense RNA genome. Filoviruses can cause severe hemorrhagic fever in humans and non-human primates. So far, only two genuses of this virus family have been identified: Marburg and Ebola. Four species of Ebola virus have been identified: Cote d'Ivoire (Cl), Sudan (S), Zaire (Z), and Reston (R). The Reston subtype is the only known filovirus that is not known to cause fatal disease in humans; however, it can be fatal in monkeys.
[0150] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Orthomyxoviridae. The family Orthomyxoviridae includes, without limitation, influenza A virus, influenza B virus, influenza C virus,
Thogotovirus, Dhori virus, and infectious salmon anemia virus. Influenza type A viruses are divided into subtypes based on two proteins on the surface of the virus. These proteins are called hemagglutinin (HA) and neuraminidase (NA). There are 15 different HA subtypes and 9 different NA subtypes. Subtypes of influenza A virus are named according to their HA and NA surface proteins, and many different combinations of HA and NA proteins are possible. For example, an “H7N2 virus” designates an influenza A subtype that has an HA 7 protein and an NA 2 protein. Similarly an “H5N1” virus has an HA 5 protein and an NA 1 protein. Only some influenza A subtypes (i.e., H1N1, H2N2, and H3N2) are currently in general circulation among people. Other subtypes such as H5 N 1 are found most commonly in other animal species and in a small number of humans, where it is highly pathogenic. For example, H7N7 and H3N8 viruses cause illness in horses. Humans can be infected with influenza types A, B, and C. However, the only subtypes of influenza A virus that normally infect people are influenza A subtypes H1N1, H2N2, and H3N2 and recently, H5N 1.
[0151] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Paramyxoviridae. The family Paramyxoviridae includes, without limitation, human parainfluenza virus, human respiratory syncytial virus (RSV), Sendai virus, Newcastle disease virus, mumps virus, rubeola (measles) virus, Hendra virus, Nipah virus, avian pneumovirus, and canine distemper virus.
[0152] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Rhabdoviridae. The family Rhabdoviridae includes, without limitation, rabies virus, vesicular stomatitis virus (VSV), Mokola virus, Duvenhage virus, European bat virus, salmon infectious hematopoietic necrosis virus, viral hemorrhagic septicaemia virus, spring viremia of carp virus, and snakehead rhabdovirus. The family Bomaviridae includes, without limitation, Boma disease virus.
[0153] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Bunyaviridae. The family Bunyaviridae includes, without limitation, Bunyamwera virus, Hantaan virus, Crimean Congo virus, California encephalitis virus, Rift Valley fever virus, and sandfly fever virus. The family Arenaviridae includes, without limitation, Old World Arenaviruses, such as Lassa virus (Lassa fever), Ippy virus, Lymphocytic choriomeningitis virus (LCMV), Mobala virus, and Mopeia virus and New World Arenaviruses, such as Junin virus (Argentine hemorrhagic fever), Sabia (Brazilian hemorrhagic fever), Amapari virus, Flexal virus, Guanarito virus (Venezuela hemorrhagic fever), Machupo virus (Bolivian hemorrhagic fever), Latino virus, Boliveros virus, Parana virus, Pichinde virus, Pirital virus, Tacaribe virus, Tamiami virus, and Whitewater Arroyo virus.
[0154] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with an arborvirus. The arboviruses are a large group (more than 400) of enveloped RNA viruses that are transmitted primarily (but not exclusively) by arthropod vectors (mosquitoes, sand-flies, fleas, ticks, lice, etc). More recently, the designated Arborviruses have been split into four virus families, including the togaviruses, flaviviruses, arenaviruses and bunyaviruses.
[0155] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a togavirus. As used herein, the term “togavirus” refers to members of the family Togaviridae, which includes the genuses Alphavirus (e.g. Venezuela equine encephalitis virus, Sindbis virus, which causes a self-limiting febrile viral disease characterized by sudden onset of fever, rash, arthralgia or arthritis, lassitude, headache and myalgia) and Rubivirus (e.g. Rubella virus, which causes Rubella in vertebrates). Flaviviridae is a member of the family of (+)-sense RNA enveloped viruses.
[0156] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Flaviviridae. Flaviviridae includes flavivirus, Pestivirus, and Hepacivirus. Flavivirus genus including yellow fever virus, dengue fever virus, and Japanese encaphilitis (JE) virus. The Pestivirus genus includes the three serotypes of bovine viral diarrhea, but no known human pathogens. Genus Hepacivirus consists of hepatitis C virus and hepatitis C-like viruses. The Japanese encephalitis antigenic complex includes Alfiiy, Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley encephalitis, St. Louis encephalitis, Stratford, Usutu, and West Nile viruses. West Nile virus is the most widespread of the flaviviruses, with geographic distribution including Africa and Eurasia. The genus Pestivirus has been divided into bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV), and border disease virus (BDV). The Hepacivirus genus includes the hepatitis C virus (HCV). [0157] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Arenaviridae. Arenaviridae is a member of the family of (-) sense RNA viruses. As used herein, the term “Arenavirus” refers to members of the genus. Arenavirius, a family of viruses whose members are generally associated with rodent- transmitted disease in humans, including Lymphocytic choriomeningitis virus (LCMV), Lassa virus, Junin virus, which causes Argentine hemorrhagic fever, Machupo virus, which causes Bolivian hemorrhagic fever, Guanarito virus, which causes Venezuelan hemorrhagic fever, and Sabia, which causes Brazilian hemorrhagic fever. LCMV causes which causes lymphocytic choriomeningitis, a mild disease that is occasionally severe with hemorrhaging.
[0158] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with the Phlebovirus Rift virus. The Phlebovirus Rift valley fever virus produces an acute, flu-like illness and is transmitted by mosquitoes from animal reservoirs (e.g. sheep) to man. Sand fly fever is transmitted to man by Phlebotomous flies (sand-flies) and causes an acute, febrile illness characterized by fever, malaise, eye pain, and headache.
[0159] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a Hendra and/or Nipah virus. Hendra and Nipah virus in the Henipavirus genus of the subfamily Paramyxovirinae are distinguished by fatal disease in both animal and human hosts.
[0160] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with ribovirus. Riboviria are all RNA viruses that replicate using RNA- dependent RNA polymerase. Examples of viruses that cause infections in humans include SARS- CoV-1, MERS-CoV, and SARS-CoV-2, 229E, NL63, OC43, KHU1.
[0161] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Herpesviridae. Herpesviridae is a large family of DNA viruses that cause disease in animals, including humans. Herpesviruses include herpes simplex virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Esptein-Barr virus, human herpesvirus 6 (variants A and B), human herpesvirus 7, and Kaposi’s sarcoma virus or human herpesvirus 8.
[0162] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Hepadnaviridae. Hepadnaviridae is a family of DNA viruses that cause hepatitis in humans and animals. Hepadnaviridae include hepatitis B virus isolated from mammals or birds.
[0163] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Papillomaviridae. Papillomaviridae is a family of non-enveloped DNA viruses with over a hundred species of papillomaviruses including Alpha papillomavirus, Beta papillomavirus, Gamma papillomavirus, Mu papillomavirus and Nupapillomavirus. HPVs are most associated with cutaneous and genital regions, cervical carcinoma and recurrent respiratory papillomatosis, among other diseases.
[0164] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a retrovirus. Human retroviruses, including human T-cell leukemia virus (HTLV-1, 2, 3 and 4) and adult T-cell leukemia virus (ATLV) Human T-lymphotropic virus cause serious diseases in humans, including adult T cell leukemia/lymphoma (ATL) and neurological disease (HTLV-associated myelopathy/tropical spastic paraparesis), uveitis, and rheumatic syndromes.
[0165] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Polyomaviridae. Polyomaviridae family of viruses are nonenveloped DNA viruses that cause disease in immunocompromised hosts. Human polyomaviruses BKV and JCV cause hemorrhagic cystitis and leukoencephalopathy. Merkel cell polyomavirus (MCPyV or MCV) shares some traits to plyomaviruses, and is thought to be linked to Merkel Cell Carcinoma (MCC), a neuroendocrine cancer.
[0166] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Poxviridae. Poxviridae is a large family of DNA viruses including molluscipoxvirus, parapoxvirus (Orf virus, pseudocowpox virus, bovine popular stomatitis virus), Orthopoxvirus (cowpox virus, monkeypox virus, vaccinia virus, variola virus), Yatapoxvirus (tanapoxvirus, yaba monkey tumor poxvirus).
[0167] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Picomaviridae. Picomaviridae are a family of viruses with single-stranded positive-sense RNA genomes and includes, without limitation, enteroviruses A through L, coxsackieviruses, echoviruses, polioviruses 1-3, and rhinoviruses A and B, hepatoviruses (Hepatitis A virus), cardioviruses (infect rodents, aphthoviruses (food-and- mouth disease virus which infects cloven-hoofed animals and occasionally humans).
[0168] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Adenoviridae. Adenoviridae is a family of double- stranded DNA viruses and include more than 100 antigenic types with human adenoviruses divided in subgenuses A-F and Serotypes 1-47, e.g. HAdV-B3, -E4, and -B7.
[0169] The compositions of the disclosure may be used in the treatment of or may be provided to a subject infected with a virus of the family Coronaviridae. Coronaviridae is a family of positive strand RNA viruses and include many of the human pathogenic CoVs such as SARS- CoV-2, SARS-CoV-1 or MERS.
[0170] In some embodiments, the present disclosure provides a method for prophylaxis or treatment of a disease, comprising administering Relacatib (GSK-462795, SB- 462795), wherein the disease is caused by a Orthomyxoviridae, influenza A virus, influenza B virus, influenza C virus, Thogotovirus, Dhori virus, infectious salmon anemia virus, Paramyxoviridae, parainfluenza virus, Sendai virus, Newcastle disease virus, mumps virus, rubeola (measles) virus, Hendra virus, avian pneumovirus, canine distemper virus, Rhabdoviridae rabies virus, vesicular stomatitis virus (VSV), Mokola virus, Duvenhage virus, European bat virus, salmon infectious hematopoietic necrosis virus, viral hemorrhagic septicaemia virus, spring viremia of carp virus, snakehead rhabdovirus, Bomaviridae, Boma disease virus, Bunyaviridae Bunyamwera virus, Crimean Congo virus, California encephalitis virus, Rift Valley fever virus, sandfly fever virus, Ippy virus, Lymphocytic choriomeningitis virus (LCMV), Mobala virus, Mopeia virus, New World Arenaviruses, Junin virus (Argentine hemorrhagic fever), Sabia (Brazilian hemorrhagic fever), Amapari virus, Flexal virus, Guanarito virus (Venezuela hemorrhagic fever), Machupo virus (Bolivian hemorrhagic fever), Latino virus, Boliveros virus, Parana virus, Pichinde virus, Pirital virus, Tacaribe virus, Tamiami virus, Whitewater Arroyo virus, arboviruses togaviruses, Sindbis virus, Rubivirus, Rubella virus, Flaviviridae, flavivirus, Pestivirus, Hepacivirus, yellow fever virus, dengue fever virus, and Japanese encaphilitis (JE) virus, Pestivirus, hepatitis C virus, hepatitis C-like viruses, Japanese encephalitis Alfiiy, Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley encephalitis, St. Louis encephalitis, Stratford, Usutu, Eastern encephalitis virus, Pestivirus, bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV), border disease virus (BDV), Arenaviridae, Lymphocytic choriomeningitis virus (LCMV), Phlebovirus Rift valley fever virus, Hendra, Riboviria, coronaviruses, SARS-CoV-2, rhinovirus, an enterovirus, a poliovirus, and an adenovirus.
VI DEFINITIONS
[0171] While the disclosure will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the disclosure to those claims. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the claims. [0172] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although suitable methods and materials are described below, methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure . In case of conflict, the patent specification, including definitions, will control. All materials, methods, and examples are illustrative only and are not intended to be limiting.
[0173] When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
[0174] About: The term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.
[0175] Absorption: “Absorption” rate is important because even when a drug is absorbed completely, it may be absorbed too slowly to produce a therapeutic blood level quickly enough or so rapidly that toxicity results from high drug concentrations given to achieve the therapeutic level after each dose. The simultaneous combination of sub-optimal doses from the drug along with one or more mammalian protease inhibitor, for example one or more cathepsin inhibitor, achieves an increase in function or efficacy of the drug, wherein the increase is any increase of about 2% and above, or between about 2%- 5%, about 5%-10%, about 10%-20%, about 20%- 30%, 10 about 30%-40%, about 40%-50%, about 50%-60%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%- 100%, about 100%-150%, about 150%-200%, about 200%- 300%, about 300%-400%, about 400%-500%, about 500%- 1000%, 1000%-5000%, about 5000%- 7000%, about 7000%- 10,000% or more, or about 0.001-fold to about 0.01 fold, about 0.05-fold to about 0.1-fold, about 0.1- fold to about 0.5-fold, about 0.5-fold to about 1- fold, about 1-fold to about 2-fold, about 3-fold to about 5-fold, about 5-fold to about 10-fold, about 10-fold to about 20-fold, about 20-fold to about 40- fold, about 50-fold to about 75-fold, about 80 fold to about 100-fold, or more, such that the effective dose is decreased for each drug mentioned in this disclosure . Effective dose is that that achieves 50% of the effect which is also termed Inhibitory Concentration 50% (IC50) or Effective Concentration (EC50) in assays in vitro, wherein the EC50 is decreased by about 5% or more, or by about 5 %- 10%, about 10%-20%, about 20%-30%, about 30%-40%, about 3040%-50%, about 50%-60%, about 60%-70%, about 70%- 80%, about 80%-90%, about 90%-100%, about 100%-150%, about 150%-200%, about 200%-300%, about 300%-400%, about 400%-500%, about 500%-1000%, 1000%-5000%, about 5000%-7000%, about 7000%-10,000% or more. In this disclosure , “sub-optimal doses” refers to doses which do not reach EC50 or IC50.
[0176] Bioavailability: “Bioavailability” is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites. The compounds of the combinations of the disclosure may be referred to as “active ingredients” or “pharmaceutically active agents.”
[0177] Bioequivalence: “Bioequivalence” refers to chemical equivalents that, when administered to the same person in the same dosage regimen, result in equivalent concentrations of drug in blood and tissues.
[0178] Chemical equivalence: “Chemical equivalence” refers to drug products that contain the same compound in the same amount and that meet current official standards. However, inactive ingredients in drug products may differ.
[0179] Clearance: “Clearance” of drug occurs by perfusion of blood to the organs of extraction. “Extraction” refers to the proportion of drug presented to the organ which is removed irreversibly (excreted) or altered to a different chemical form (metabolism). Clearance (CL) is therefore calculated as the product of the flow of blood through the organ and proportion of the drug extracted by the organ.
[0180] Comprising: As used herein, the terms “comprising“ and “including” or grammatical variants thereof are to be taken as specifying inclusion of the stated features, integers, actions or components without precluding the addition of one or more additional features, integers, actions, components or groups thereof. This term is broader than, and includes the terms “consisting of’ and “consisting essentially of’ as defined by the Manual of Patent Examination Procedure of the United States Patent and Trademark Office. Thus, any recitation that an embodiment “includes” or “comprises” a feature is a specific statement that sub embodiments “consist essentially of’ and/or “consist of’ the recited feature. As used herein, the term “comprises” means “includes, but is not limited to”.
[0181] Effective Amount: As used herein, the term “effective amount”, “effective concentration”, or “effective dose” means an amount that is sufficient upon appropriate administration to a patient (a) to cause a detectable decrease in the severity of the disorder or disease state being treated; (b) to ameliorate or alleviate the patient's symptoms of the disease or disorder; or (c) to slow or prevent advancement of, or otherwise stabilize or prolong stabilization of, the disorder or disease state being treated. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the patient, time of administration, rate of excretion, drug combinations, the judgment of the treating physician, and the severity of the particular disease being treated.
[0182] Maximum tolerated dose: As used herein, the “maximum tolerated dose” (MTD) is the highest possible but still tolerable dose level with respect to a pre-specified clinical limiting toxicity. In general, these limits refer to the average patient population. For instances in which there is a large difference between the MED and MTD, it is stated that the drug has a large therapeutic window. Conversely, if the range is relatively small, or if the MTD is less than the MED, then the pharmaceutical product will have little to no practical value.
[0183] Method: The term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of chemistry and/or pharmacology.
[0184] Minimum effective dose: As used herein, the “minimum effective dose” (MED) is defined as the lowest dose level of a pharmaceutical product that provides a clinically significant response in average efficacy, which is also statistically significantly superior to the response provided by the placebo.
[0185] Physiologically functional derivative: The term “physiologically functional derivative” means a pharmaceutically active compound with equivalent or near equivalent physiological functionality when administered in combination with another pharmaceutically active compound in a combination of the disclosure . As used herein, the term “physiologically functional derivative” includes any: physiologically acceptable salt, ether, ester, prodrug, solvate, stereoisomer including enantiomer, diastereomer or stereoisomerically enriched or racemic mixture, and any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
[0186] Potentiating: The term “potentiating” effect as used herein refers to and enhancement of the effect or action of an agent, a drug, or a chemical. A potentiating agent can be a chemical, an agent or a drug that enhances or intensifies an effect or action of another agent, chemical or drug.
[0187] Prodrug: The term “prodrug” as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). “Prodrug moiety” means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
[0188] Side effects: “Side effects” or “toxicity” or “adverse drug reactions” of drugs are effects which may be minor, severe, quite severe, or disabling and may be reversible or irreversible. In medicine, a side effect is an adverse effect that is secondary to the one intended consequence and otherwise described as an unintended, consequences of the use of a drug whether in the targeted or untargeted parts of the body.
[0189] Subject: As used herein, the term “subject” or “patient” is a mammal, and examples thereof include human, dog, cat, bovine, horse, swine and the like, with preference given to human.
[0190] Synergy: The terms “synergy” and “synergistic” mean that the effect achieved when the drug and compound are used together is greater than the sum of the effects that results from using the drug and the compound separately, i.e. greater than what would be predicted based on the two active ingredients administered separately. A synergistic effect may be attained when the drug and compound are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the drug and compound are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual active ingredients of the combination. [0191] Therapeutic equivalence: “Therapeutic equivalence” refers to drug products that, when administered to the same person in the same dosage regimen, provide essentially the same therapeutic effect or toxicity. Bioequivalent products are expected to be therapeutically equivalent. Sometimes therapeutic equivalence may be achieved despite differences in bioavailability, for example when the therapeutic index is wide (ratio of maximum tolerated dose to the minimum effective dose). [0192] Treatment: As used herein, the term “treatment” means treating a patient having, or at risk of developing or experiencing a recurrence of the relevant disorder being treated, including suppression of progression of the relevant disorder being treated.
[0193] In order that this disclosure be more fully understood, the following preparative and testing examples are set forth. These examples illustrate how to make or test specific compounds and are not to be construed as limiting the scope of the disclosure in any way.
[0194] Techniques for practicing the specific aspect of this disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, and recombinant DNA manipulation and production, which are routinely practiced by one of skill in the art. See, e.g., Sambrook et ah, Molecular cloning, a laboratory manual, second ed., vol. 1-3. (Cold Spring Harbor Laboratory, 1989), A Laboratory Manual, Second Edition; DNA Cloning, Volumes I and II (Glover, Ed. 1985); and Transcription and Translation (Hames & Higgins, Eds. 1984). Western blot analysis or Northern blot analysis or any other technique used for the quantification of transcription of a nucleotide sequence, the abundance of its mRNA its protein (see Short Protocols in Molecular Biology, Ausubel et ah, (editors), John Wiley & Sons, Inc., 4.sup.th edition, 1999; Current Protocols in Molecular Biology, volume 1-3 (1994-1998). Ed. by Ausubel, F. M., Brent, R., Kunston, R. E., Moore, D. D., Seidman, J. G., Smith, J. A. and Struhl, K. Published by John Wiley and sons, Inc., USA, Greene Publish. Assoc. & Wiley Interscience), (Short Protocols in Molecular Biology, 1999, Ed. Ausubel et ah, John Wiley & Sons, Inc., Unit 10.11) etc. The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred materials and methods are now described. Other features, objects and advantages of the disclosure will be apparent from the description. In the description, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present description will control.
[0195] The present disclosure is further illustrated by the following non-limiting examples. EXAMPLES
Example 1. Testing for synergistic compounds
[0196] The disclosure provides methods for the identification of a compound that produces synergistic activity with a drug of choice. In certain aspects, the disclosure provides methods for the identification of a compound that reduces the effective dosage of a drug of choice. Any technique well-known to the skilled artisan can be used to screen for a compound that would reduce the effective dose of a drug. As an example, a cell is contacted with a test mammalian protease inhibitor in combination with a drug of choice, for example an antiviral drug. A control without the test mammalian protease inhibitor is provided. The cell can be contacted with a test mammalian protease inhibitor before, concurrently with, or subsequent to the administration of the drug. In certain embodiments, the cell is incubated with multiple concentrations of the drug and test mammalian protease inhibitor, for at least 1 minute to at least during the experiment. The effect of the combination on the viral replication is measured at any time during the assay. In certain embodiments, a time course of viral growth in the culture is determined. If the viral growth is inhibited or reduced in the presence of the test compound at reduced drug concentrations wherein the effect is more than an additive effect, the test mammalian protease inhibitor is identified as being effective in producing a synergistic activity.
Example 2. Assays for evaluating the combinations
[0197] The combinations of the disclosure may be tested for in vitro activity against a disease or microorganism and sensitivity, and for cytotoxicity in laboratory adapted cell lines or cultured cells such as peripheral blood mononuclear cells (PBMC), human fibroblast cells, hepatic, renal, epithelium cells, according to standard assays developed fortesting compounds. Combination assays may be performed at varying concentrations of the compounds of the combinations to determine EC 50 by serial dilutions.
In vitro assays
[0198] Cells: HEp-2 (CCL-23), PC-3 (CCL-1435), HeLa (CCL-2), U20S (HTB-96), Vero (CCL-81), HFF-1 (SCRC- 1041),Calu-3, Hela cells with human ACE-2, Hu7.5 cells, MRC5 cells and HepG2 (HB-8065) cell lines can be purchased from the American Type Culture Collection. HEp-2 cells can be cultured in Eagle’s Minimum Essential Media (MEM) with GlutaMAX supplemented with 10% fetal bovine serum (FBS) and 100 U ml-1 penicillin and streptomycin. PC-3 cells can be cultured in Kaighn’s F12 media supplemented with 10% FBS and 100 U ml-1 penicillin and streptomycin. HeLa, U20S, and Vero cells can be cultured in MEM supplemented with 10% FBS, 1% L-glutamine, 10 mM HEPES, 1% non-essential amino acids, and 1% penicillin/streptomycin. HFF-1 cells can be cultured in MEM supplemented with 10% FBS and 0.5 mM sodium pyruvate. HepG2 cells can be cultured in Dulbecco’s Modified Eagle Medium (DMEM) with GlutaMAX supplemented with 10% FBS, 100 U ml-1 penicillin and streptomycin, and 0.1 mM non-essential amino acids. The MT-4 cell line can be obtained from the NIH AIDS Research and Reference Reagent Program and cultured in RPMI-1640 medium supplemented with 10% FBS, 100 U ml-1 penicillin and streptomycin, and 2 mM L glutamine. The Huh-7 cell line can be obtained from C. M. Rice (Rockefeller University) and cultured in DMEM supplemented with 10% FBS, 100 U ml-1 penicillin and streptomycin, and non-essential amino acids. Primary human hepatocytes or other primary cell can be purchased from Invitrogen and cultured in William’s Medium E medium containing cell maintenance supplement. Donor profdes will be limited to 18- to 65-year-old nonsmokers with limited alcohol consumption.
Upon delivery, the cells will be allowed to recover for 24 h in complete medium with supplement provided by the vendor at 37°C. Human PBMCs will be isolated from human huffy coats obtained from healthy volunteers (Stanford Medical School Blood Center, Palo Alto, California) and maintained in RPMI-1640 with GlutaMAX supplemented with 10% FBS, 100 U ml-1 penicillin and streptomycin. To test viral inhibition in primary nonhuman primate cells, Rhesus fresh whole blood will be obtained from Valley Biosystems or other suppliers. PBMCs will be isolated from whole blood by Ficoll Hypaque density gradient centrifugation. Briefly, blood will be overlaid on 15 ml Ficoll-Paque (GE Healthcare Bio-Sciences AB), and centrifuged at 500g for 20 min. The top layer containing platelets and plasma will be removed, and the middle layer containing PBMCs will be transferred to a fresh tube, diluted with Tris buffered saline up to 50 ml, and centrifuged at 500g for 5 min. The supernatant will be removed and the cell pellet will be resuspended in 5 ml red blood cell lysis buffer (155 mM ammonium chloride, 10 mM potassium bicarbonate, 0.1 mM EDTA, pH 7.5). To generate stimulated PBMCs, freshly isolated quiescent PBMCs will be seeded into a T-150 (150 cm2) tissue culture flask containing fresh medium supplemented with 10 U ml-1 of recombinant human interleukin-2 (IL-2) and 1 pg ml-1 phytohaemagglutinin-P at a density of 2 c 106 cells ml-1 and incubated for 72 h at 37°C. Human macrophage cultures will be isolated from PBMCs that will be purified by Ficoll gradient centrifugation from 50 ml of blood from healthy human volunteers. PBMCs will be cultured for 7 to 8 days in in RPMI cell culture media supplemented with 10% FBS, 5 to 50 ng ml-1 granulocyte-macrophage colony-stimulating factor and 50 mM b- mercaptoethanol to induce macrophage differentiation. The cryopreserved human primary renal proximal tubule epithelial cells will be obtained from FifeFine Cell Technology and isolated from the tissue of human kidney. The cells will be cultured at 90% confluency with RenaFife complete medium in a T-75 flask for 3 to 4 days before seeding into 96-well assay plates. Immortalized human microvascular endothelial cells (HMVEC-TERT) will be obtained from R. Shao at the Pioneer Valley Fife Sciences Institute. HMVEC-TERT cells will be cultured in endothelial basal media supplemented with 10% FBS, 5 pg of epithelial growth factor, 0.5 mg hydrocortisone, and gentamycin/amphotericin-B. In some experiments it may be essential to evaluate the intracellular metabolism (phosphorylation) of nucleobase and nucleoside (Nuc) these studies will be performed as below. The intracellular metabolism of nucleoside will be assessed in different cell types (HMVEC and HeLa cell lines, and primary human and rhesus PBMCs, monocytes and monocyte-derived macrophages) following 2-h pulse or 72-h continuous incubations with 10- 1,000 mM of nucleobase or nucleoside. For comparison, intracellular metabolism during a 72-h incubation with 10-1,000 pM of Nuc will be completed in human monocyte -derived macrophages. For pulse incubations, monocyte-derived macrophages isolated from rhesus monkeys or humans will be incubated for 2h in compound-containing media followed by removal, Uimethylhexylamine (DMH) in water for analysis by liquid chromatography coupled to triple quadrupole mass spectrometry (FC-MS/MS). FC-MS/MS will be performed using low- flow ionpairing chromatography, similar to methods described previously (Durand-Gasselin F, et al. Nucleotide analogue prodrug tenofovir disoproxil enhances lymphoid cell loading following oral administration in monkeys. Mol. Pharm. 2009; 6: 1145-1151). Briefly, analytes will be separated using a 50 c 2 mm c 2.5 pm Funa Cl 8(2) HST column (Phenomenex) connected to a FC-20ADXR (Shimadzu) ternary pump system and HTS PAF autosampler (FEAP Technologies). A multi-stage linear gradient from 10% to 50% acetonitrile in a mobile phase containing 3 mM ammonium formate (pH 5.0) with 10 mM dimethylhexylamine over 8 min at a flow rate of 150 pi min-1 will be used to separate analytes. Detection will be performed on an API 4000 (Applied Biosystems) MS/MS operating in positive ion and multiple reaction monitoring modes. Intracellular metabolites alanine metabolite, Nuc, nucleoside monophosphate, nucleoside diphosphate, and nucleoside triphosphate will be quantified using 7- point standard curves ranging from 0.274 to 200 pmol (approximately 0.5 to 400 pM) prepared in cell extract from untreated cells. Fevels of adenosine nucleotides will be also quantified to assure dephosphorylation had not taken place during sample collection and preparation. In order to calculate intracellular concentration of metabolites, the total number of cells per sample will be counted using a Countess automated cell counter (Invitrogen).
Ebola Antiviral testing using Huh-7 and HMVEC
[0199] Antiviral assays can be conducted in a biosafety level 4 containment (BSF-4), for example at the Centers for Disease Control and Prevention. EBOV antiviral assays will be conducted in primary HMVEC-TERT and in Huh-7 cells. Huh-7 cells will not be authenticated and will not be tested for mycoplasma. Ten concentrations of compound will be diluted in fourfold serial dilution increments in media, and 100 pi per well of each dilution will be transferred in duplicate (Huh-7) or quadruplicate (HMVEC-TERT) onto 96-well assay plates containing cell monolayers. The plates will be transferred to BSF-4 containment, and the appropriate dilution of virus stock will be added to test plates containing cells and serially diluted compounds. Each plate will include four wells of infected untreated cells and four wells of uninfected cells that serve as 0% and 100% virus inhibition controls, respectively. After the infection, assay plates will be incubated for 3 days (Huh-7) or 5 days (HMVEC-TERT) in a tissue culture incubator. Virus replication will be measured by direct fluorescence using a Biotek HTSynergy plate reader. For virus yield assays, Huh- 7 cells will be infected with wild-type EBOV for 1 h at 0.1 plaque-forming units (PFU) per cell. The virus inoculum will be removed and replaced with 100 mΐ per well of media containing the appropriate dilution of compound. At 3 days post-infection, supernatants will be collected, and the amount of virus will be quantified by endpoint dilution assay. The endpoint dilution assay will be conducted by preparing serial dilutions of the assay media and adding these dilutions to fresh Vero cell monolayers in 96-well plates to determine the tissue culture infectious dose that caused 50% cytopathic effects (TCID50). To measure levels of viral RNA from infected cells, total RNA will be extracted using the MagMAX-96 Total RNA Isolation Kit and quantified using a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay with primers and probes specific for the EBOV nucleoprotein gene. Assay in HeLa and HFF-1 cells Antiviral assays will be conducted in BSL-4. HeLa or HFF-1 cells will be seeded at 2,000 cells per well in 384-well plates. Ten serial dilutions of compound in triplicate will be added directly to the cell cultures using the HP D300 digital dispenser (Hewlett Packard) in twofold dilution increments starting at 10 mM at 2 h before infection. The DMSO concentration in each well will be normalized to 1% using an HP D300 digital dispenser. The assay plates will be transferred to the BSL-4 suite and infected with EBOV Kikwit at a multiplicity of infection of 0.5 PFU per cell for HeLa cells and with EBOV Makona at a multiplicity of infection of 5 PFU per cell for HFF-1 cells. The assay plates will be incubated in a tissue culture incubator for 48 h. Infection will be terminated by fixing the samples in 10% formalin solution for an additional 48 h before immunostaining, as described.
EBOV human macrophage infection assay
[0200] Antiviral assays will be conducted in BSL-4. Primary human macrophage cells will be seeded in a 96-well plate at 40,000 cells per well. Eight to ten serial dilutions of compound in triplicate will be added directly to the cell cultures using an HP D300 digital dispenser in threefold dilution increments 2 h before infection. The concentration of DMSO will be normalized to 1% in all wells. The plates will be transferred into the BSL-4 suite, and the cells will be infected with 1 PFU per cell of EBOV in 100 mΐ of media and incubated for 1 h. The inoculum will be removed, and the media will be replaced with fresh media containing diluted compounds. At 48 h post infection, virus replication will be quantified by immuno-staining. RSV A2 antiviral assay
[0201] For antiviral tests, compounds will be threefold serially diluted in source plates from which 100 mL. of diluted compound will be transferred to a 384-well cell culture plate using an Echo acoustic transfer apparatus. HEp-2 cells will be added at a density of 5 c 105 cells per ml, then infected by adding RSV A2 at a titer of 1 c 104 tissue culture infectious doses (TCID50) per ml. Immediately following virus addition, 20 mΐ of the virus and cells mixture will be added to the 384-well cell culture plates using a pFlow liquid dispenser and cultured for 4 days at 37°C. After incubation, the cells will be allowed to equilibrate to 25°C for 30 min. The RSV-induced cytopathic effect will be determined by adding 20 mΐ of CellTiter-Glo Viability Reagent. After a 10-min incubation at 25°C, cell viability will be determined by measuring luminescence using an Envision plate reader.
High content imaging assay detecting viral infection
[0202] Antiviral assays will be conducted in 384-or 96-well plates in BSL-4 using a high- content imaging system to quantify virus antigen production as a measure of virus infection. A ‘no virus’ control and a ‘ 1% DMSO’ control will be included to determine the 0% and 100% virus infection, respectively. The primary and secondary antibodies and dyes used for nuclear and cytoplasmic staining are listed. The primary antibody specific for a particular viral protein will be diluted 1,000-fold in blocking buffer (1 c PBS with 3% BSA) and added to each well of the assay plate. The assay plates will be incubated for 60 min at room temperature. The primary antibody will be removed, and the cells will be washed three times with 1 c PBS. The secondary detection antibody will be an anti-mouse (or rabbit) IgG conjugated with Dylight488 (Thermo Fisher Scientific, catalogue number 405310). The secondary antibody will be diluted 1,000-fold in blocking buffer and will be added to each well in the assay plate. Assay plates will be incubated for 60 min at room temperature. Nuclei will be stained using Draq5 (Biostatus) or 33342 Hoechst (ThermoFisher Scientific) for Vero and HFF-1 cell lines. Both dyes will be diluted in lx PBS. The cytoplasm of HFF-1 (EBOV assay) and Vero E6 (MERS assay) cells will be counter-stained with CellMask Deep Red (Thermo Fisher Scientific). Cell images will be acquired using a Perkin Elmer Opera confocal plate reader (Perkin Elmer) using a c 10 air objective to collect five images per well. Virus-specific antigen will be quantified by measuring fluorescence emission at a 488 nm wavelength and the stained nuclei will be quantified by measuring fluorescence emission at a 640 nm wavelength. Acquired images will be analyzed using Harmony and Acapella PE software. The Draq5 signal will be used to generate a nuclei mask to define each nucleus in the image for quantification of cell number. The CellMask Deep Red dye will be used to demarcate the Vero and HFF-1 cell borders for cell-number quantitation. The viral-antigen signal will be compartmentalized within the cell mask. Cells that exhibited antigen signal higher than the selected threshold will be counted as positive for viral infection. The ratio of virus positive cells to total number of analyzed cells will be used to determine the percentage of infection for each well on the assay plates. The effect of compounds on the viral infection will be assessed as percentage of inhibition of infection in comparison to control wells. The resultant cell number and percentage of infection will be normalized for each assay plate. Analysis of dose- response curve will be performed using GeneData Screener or similar software applying Levenberg- Marquardt algorithm for curve-fitting strategy. The curve-fitting process, including individual data point exclusion, will be pre-specified by default software settings. R2 value quantified goodness of fit and fitting strategy will be considered acceptable at R2 > 0.8. Virus assays
[0203] All virus infections will be quantified by immuno-staining using antibodies that recognized the relevant viral glycoproteins.
Marburg virus assay
[0204] HeLa cells will be seeded at 2,000 cells per well in a 384-well plate, and compounds will be added to the assay plates. Assay plates will be transferred to the BSL-4 suite and infected with 1 PFU per cell MARV, which resulted in 50% to 70% of the cells expressing virus antigen in a 48-h period.
Sudan virus assay
[0205] HeLa cells will be seeded at 2,000 cells per well in a 384-well plate, and compounds will be added to the assay plates. Assay plates will be transferred to the BSL-4 suite and infected with 0.08 PFU SUDV per cell, which resulted in 50% to 70% of the cells expressing virus antigen in a 48-h period.
Junin virus assay
[0206] HeLa cells will be seeded at 2,000 cells per well in a 384-well plate, and compounds will be added to the assay plates. Assay plates will be transferred to the BSL-4 suite and infected with 0.3 PFU per cell JUNV, which resulted in -50% of the cells expressing virus antigen in a 48-h period.
Lassa fever virus assay
[0207] HeLa cells will be seeded at 2,000 cells per well in a 384-well plate, and compounds will be added to the assay plates. Assay plates will be transferred to the BSL-4 suite and infected with 0.1 PFU per cell LASV, which resulted in >60% of the cells expressing virus antigen in a 48-h period. Middle East respiratory syndrome, SARS-CoVl, and SARS-CoV-2 assays [0208] African green monkey (Chlorocebus sp.) kidney epithelial cells (Vero E6) will be seeded at 4,000 cells per well in a 384-well plate, and compounds will be added to the assay plates in a dose dependent manner. Assay plates will be transferred to the BSL-3/4 suite and infected with 0.5 or other PFU per cell of MERS, SARS-CoVl and 2 virus, which resulted in >70% of the cells expressing virus antigen in a 48-h period.
SARS-CoV-2 infection assay
[0209] Calu-3 cells (1 c 104 cells) can be seeded in 96 well plate. After 24 h, cells will be washed and treated with inhibitor (s) in a serum-free medium (n=6). The incubation of cells with media alone will serve as a negative control (n=6). After 2-16 h of inhibitor(s) treatment, cells will be washed and replaced with serum-free media for infection with SARS-CoV-2 (strain: BEI_USA-WAl/2020) multiplicity of infection (MOI) of 0.01 for 1 h at 37°C. After infection, cells will be washed and replaced with 5% FBS containing media. After 48-72 h post-infection, cells will be fixed with 4% buffered paraformaldehyde for 15 min at room temperature. The fixed cells will be washed with PBS then permeabilized in 0.1% Triton X100 PBS solution for 15 min then blocked in 3% BSA PBS solution. The cells will be incubated with anti-S protein Rab (Sino Biological, PA, USA) at 1: 1000 in the blocking solution overnight at 4°C, followed by incubation with 1:2000 diluted Alexa Fluor 488 conjugated secondary antibody (Thermo Fisher, MA, USA) for 1 h at room temperature. The cells will be counterstained for nuclei with Hoechst 33342 (Thermo Fisher, MA, USA). The fluorescent images will be captured by using a Nikon Eclipse Ts2R fluorescent microscope or other plate readers such as Operetta or Opera. Total and virus-infected cells will be counted by using Nikon NIS-Elements D software. High content imaging assays will be performed as described herein.
Chikungunya virus assay
[0210] U20S cells will be seeded at 3,000 cells per well in a 384-well plate, and compounds will be added to the assay plates. Assay plates will be transferred to the BSE suite and infected with 0.5 PFU per cell of CHIK, which resulted in >80% of the cells expressing virus antigen in a 48-h period.
Venezuelan equine encephalitis virus assay
[0211] HeFa cells will be seeded at 4,000 cells per well in a 384-well plate, and compounds will be added to the assay plates. Assay plates will be transferred to the BSF-4 suite and infected with 0.1 PFU per cell VEEV, which resulted in >60% of the cells expressing virus antigen in a 20-h period. Cytotoxicity assays
[0212] HEp-2 (1.5 c 103 cells per well) and MT-4 (2 c 103 cells per well) cells will be plated in 384- well plates and incubated with the appropriate medium containing threefold serially diluted compound ranging from 15 nM to 100,000 nM. PC-3 cells (2.5 c 103 cells per well), HepG2 cells (4 c 103 cells per well), hepatocytes (1 c 106 cells per well), quiescent PBMCs (1 c 106 cells per well), stimulated PBMCs (2 c 105 cells per well), and RPTEC cells (1 c 103 cells per well) will be plated in 96- well plates and incubated with the appropriate medium containing threefold serially diluted compound ranging from 15 nM to 100,000 nM. Cells will be cultured for 4-5 days at 37 °C. Following the incubation, the cells will be allowed to equilibrate to 25°C, and cell viability will be determined by adding Cell-Titer Glo viability reagent. The mixture will be incubated for 10 min, and the luminescence signal will be quantified using an Envision plate reader. Cell lines will be not authenticated and will be not tested for mycoplasma as part of routine use in cytotoxicity assays. For RSV, In vitro RSV RNA synthesis assay will be used RNA synthesis by the RSV polymerase will be reconstituted in vitro using purified RSV L/P complexes and an RNA oligonucleotide template (Dharmacon), representing nucleotides 1-14 of the RSV leader promoter (3'-UGCGCUUUUUUACG-5'). RNA synthesis reactions will be performed as described previously, except that the reaction mixture contained 250 mM guanosine triphosphate (GTP), 10 pM uridine triphosphate (UTP), 10 pM cytidine triphosphate (CTP), supplemented with 10 pCi [a- 32P]CTP, and either included 10 pM adenosine triphosphate (ATP) or no ATP. Under these conditions, the polymerase is able to initiate synthesis from the position 3 site of the promoter, but not the position 1 site. The NTP metabolite of GS-5734 will be serially diluted in DMSO and included in each reaction mixture at concentrations of 10, 30, or 100 pM as specified. RNA products will be analyzed by electrophoresis on a 25% polyacrylamide gel, containing 7 M urea, in Tris- taurine-EDTA buffer, and radiolabeled RNA products will be detected by autoradiography.
RSV A2 polymerase inhibition assay
[0213] Transcription reactions contained 25 pg of crude RSV RNP complexes in 30 pL of reaction buffer (50 mM Tris-acetate (pH 8.0), 120 mM potassium acetate, 5% glycerol, 4.5 mM MgC12, 3 mM DTT, 2 mM EGTA, 50 pg ml-1 BSA, 2.5 U RNasin, 20 pM ATP, 100 pM GTP, 100 pM UTP, 100 pM CTP, and 1.5 pCi [a-32P]ATP (3,000 Ci mmol-1). The radiolabeled nucleotide used in the transcription assay will be selected to match the nucleotide analogue being evaluated for inhibition of RSV RNP transcription. To determine whether nucleotide analogues inhibited RSV RNP transcription, compounds will be added using a six-step serial dilution in fivefold increments. After a 90-min incubation at 30°C, the RNP reactions will be stopped with 350 mΐ of Qiagen RLT lysis buffer, and the RNA will be purified using a Qiagen RNeasy 96 kit. Purified RNA will be denatured in RNA sample loading buffer at 65 °C for 10 min and run on a 1.2% agarose/MOPS gel containing 2 M formaldehyde. The agarose gel will be dried, exposed to a Storm phosphorimaging screen, and developed using a Storm phosphorimager.
Equivalents and Scope
[0214] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims.
[0215] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process.
[0216] It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of’ is thus also encompassed and disclosed.
[0217] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[0218] In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art. [0219] It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects.
[0220] While the present disclosure has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the disclosure.

Claims (68)

CLAIMS What is claimed is:
1. A method of improving the efficacy of a drug in a subject, said method comprising combining the drug with a mammalian protease inhibitor, wherein the efficacy of the drug is improved by the combination of the drug with the mammalian protease inhibitor which produces a synergistic or additive activity, and wherein the subject has a viral infection caused by a coronavirus.
2. A method of lowering the toxicity of a drug in a subject, said method comprising combining the drug with a mammalian protease inhibitor, wherein the toxicity of the drug is lowered by the combination of the drug with the mammalian protease inhibitor which produces a synergistic or additive activity, and wherein the subject has a viral infection caused by a coronavirus.
3. A method of reducing the dose of a drug in a subject, said method comprising administering said drug in combination with a mammalian protease inhibitor, wherein the dose of the drug is reduced by the combination of the drug with the mammalian protease inhibitor which produces a synergistic or additive activity, and wherein the subject has a viral infection caused by a coronavirus.
4. The method of any one of claims 1- 3, wherein the mammalian protease inhibitor is a cathepsin inhibitor.
5. The method of claim 4, wherein the cathepsin inhibitor is a cysteine cathepsin inhibitor.
6. The method of any one of claims 1-5, wherein the cathepsin inhibitor is a cathepsin-B inhibitor, a cathepsin-L inhibitor, a cathepsin-S inhibitor, a cathepsin-F inhibitor, a cathepsin-X inhibitor, a cathepsin-K inhibitor, a cathepsin-V inhibitor, a cathepsin-W inhibitor, a cathepsin-C inhibitor, a cathepsin-0 inhibitor, or a cathepsin-H inhibitor.
7. The method of any one of claims 1-6, wherein the cathepsin inhibitor is Balicatib (AAE581), E-64, E-64a, E-64b, E-64c; E-64d; CA-074; CA-074 Me; CA-030; CA-028; peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac-LYK-CHO, Z-Phe-Tyr-CHO, Z-Phe-Tyr(OtBu)- C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp-CHO, Z-Phe-Leu-C0CH0.H20, peptidyl semicarbazone derivatives, peptidyl methylketone derivatives, peptidyl trifluoromethylketone derivatives, Biotin- Phe-Ala-fluoromethyl ketone, Z-Leu-Leu-Leu-fluoromethyl ketone, Z-Phe- Phe-fluoromethyl ketone, N-Methoxysuccinyl-Phe-HOMO-Phe-fluoromethyl ketone, Z-Leu- Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone, peptidylchloromethases, peptidylhydroxymates, peptidylhydroxylamines, peptidyl acyloxymethanes, peptidylacyloxymethyl ketones, peptidyl aziridines, peptidyl aryl vinylsufones; peptidyl arylvinylsulfonates, gallinamide analogs, peptidyl aldehydes, azepinone-based inhibitors, nitrile- containing inhibitors, thiosemicarbazone, propeptide mimics, thiocarbazate, oxocarbazate, azapaptides, peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ- Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala-CHN2, Z-Phe-Thr(OBzl)-CHN2, Z- Phe-Tyr (Ot-But)-CHN2, Z-Leu-Leu-Tyr-CHN2, peptidyl acyloxymethyl ketones, peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS, peptidyl nitriles, peptidyl disulfides, 5,5'- dithiobis[2-nitrobenzoic acid], cysteamines, 2,2'-dipyridyldisulfide, non-covalent inhibitors, N- (4-Biphenylacetyl)-S-methyl cysteine-(D)-Arg-Phe-bl phenethylamide, thiol alkylating agents, maleimides, azapeptides, azobenzenes, O-acylhydroxamates, Z-Phe-Gly-NHO-Bz, Z-FG-NHO- BzOME, lysosomotropic agents, chloroquine, ammonium chloride, Cystatin A, Cystatin B, Cystatin C, Cystatin D, Cystatin F, stefins, kininogens, Sialostain L, antimicrobial peptide LL-37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50; Odanacatib (MK-0822), Relacatib (GSK-462795, SB-462795), SLV213 (K777 ORK1777), RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517, ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY- 106; VBY-285;VBY-825), VBY-129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV- 30247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI- 1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY-210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP- 0015962), SAR-164653, KGP94, VEL-0230, BLD2660 or derivatives thereof.
8. The method of claim 7, wherein the cathepsin inhibitor is Balicatib (AAE581).
9. The method of any one of claims 1- 8, wherein the drug is an antiviral drug.
10. The method of claim 9, wherein the antiviral drug is a nucleoside analog, a nucleotide analog, a viral protease inhibitor, a viral polymerase inhibitor, a reverse transcriptase inhibitor, a viral envelope fusion inhibitor, a prophylactic agent, a protein drug, a proton transport inhibitor, or a neuraminidase inhibitor.
11. The method of claim 10, wherein the antiviral drug is a nucleoside analog.
12. The method of claim 11, wherein the nucleoside analog is T-705 (Avigan, Favipiravir), BCX4430 (Galidesivir), Brincidofovir, FGE-106, JK-05, Nafamostet, Triazavirin, Acyclovir Fleximer, Ribavirin, AL-335 (Adafosbuvir), 6-azauridine, gancyclovir, dideocycytidine, dideoxyinosine, GS-5734 (Remdesivir), JNJ-64041575, JNJ-1575, ALS-008176, AL-8176 (Lumicitabine), Hepsera (adefovir dipivoxil), Peveon, Viread (tenofovir disoproxil fumarate), Acycloadenosine (predecessor of acyclovir), NITD008, MK-608, ribonucleoside analog -d-N4- hydroxycytidine (NHC; EIDD-1931), EIDD-2801 (Molnupiravir), AT-527, AT-511, or resimiquid.
13. The method of claim 12, wherein the nucleoside analog is T-705 (Avigan, Favipiravir).
14. The method of claim 10, wherein the antiviral drug is a nucleotide analog.
15. The method of claim 10, wherein the antiviral drug is a viral protease inhibitor.
16. The method of claim 15, wherein the viral protease inhibitor is PF-07321332, PF-07304814, PF-00835231, atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), darunavir/cobicistat (Prezcobix), asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, or telaprevir.
17. The method of claim 10, wherein the antiviral drug is a viral polymerase inhibitor.
18. The method of claim 17, wherein the viral polymerase inhibitor is EIDD-2801 (Molnupiravir), AT-527, AT-511, Foscamet, Cidofovir, or Alovudine.
19. The method of claim 10, wherein the antiviral drug is a reverse transcriptase inhibitor.
20. The method of claim 19, wherein the reverse transcriptase inhibitor is Nevirapine, Delavirdine, Efavirenz, Etravirine, Etravirine, Rilpivirine, Adefovir dipivoxil, or Atevirdine.
21. The method of claim 10, wherein the antiviral drug is a viral envelope fusion inhibitor.
22. The method of claim 21, wherein the viral envelope fusion inhibitor is Docosanol, Enfuvirtide, or Maraviroc.
23. The method of claim 10, wherein the antiviral drug is a prophylactic agent.
24. The method of claim 23, wherein the prophylactic agent is RSV-IGIV, VZIG, or VariZIG.
25. The method of claim 10, wherein the antiviral drug is a protein drug.
26. The method of claim 25, wherein the protein drug is an antibody.
27. The method of claim 10, wherein the antiviral drug is a proton transport inhibitor.
28. The method of claim 27, wherein the proton transport inhibitor is Rimantadine or Methisazone.
29. The method of claim 10, wherein the antiviral drug is a neuraminidase inhibitor.
30. The method of claim 29, wherein the neuraminidase inhibitor is Zanamivir, Oseltamivir, Laninamivir octanoate, or Peramivir.
31. The method of claim 1, wherein the coronavirus is SARS-CoV-2, SARS-CoV-1, or MERS- CoV.
32. A composition comprising an antiviral drug and a mammalian protease inhibitor.
33. The composition of claim 32, wherein the mammalian protease inhibitor is a cathepsin inhibitor.
34. The composition of claim 32, wherein the antiviral drug is a nucleoside analog, a nucleotide analog, viral protease inhibitor, a viral polymerase inhibitor, a reverse transcriptase inhibitor, a viral envelope fusion inhibitor, a prophylactic agent, a protein drug, a proton transport inhibitor, or a neuraminidase inhibitor.
35. The composition of claim 34, wherein the antiviral drug is a nucleoside analog.
36. The composition of claim 35, wherein the nucleoside analog is T-705 (Avigan, Favipiravir),
BCX4430 (Galidesivir), Brincidofovir, FGE-106, JK-05, Triazavirin, Acyclovir Fleximer, Ribavirin, AL-335 (Adafosbuvir), 6-azauridine, gancyclovir, dideocycytidine, dideoxyinosine, GS-5734 (Remdesivir), JNJ-64041575, JNJ-1575, ALS-008176, AL-8176 (Lumicitabine), Hepsera (adefovir dipivoxil), Peveon, Viread (tenofovir disoproxil fumarate), Acycloadenosine (predecessor of acyclovir), NITD008, MK-608, ribonucleoside analog -d-N4-hydroxycytidine (NHC; EIDD-1931), EIDD- 2801 EIDD-2801 (Molnupiravir), AT-527, AT-511,or resimiquid.
37. The composition of claim 35, wherein the nucleoside analog is T-705 (Avigan, Favipiravir).
38. The composition of claim 34, wherein the antiviral drug is a nucleotide analog.
39. The composition of claim 34, wherein the antiviral drug is a viral protease inhibitor.
40. The composition of claim 39, wherein the viral protease inhibitor is PF-07321332, PF- 07304814, PF-00835231, atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfmavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus), atazanavir/cobicistat (Evotaz), darunavir/cobicistat (Prezcobix), asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, or telaprevir.
41. The composition of claim 34, wherein the antiviral drug is a viral polymerase inhibitor.
42. The composition of claim 41, wherein the viral polymerase inhibitor is Foscamet, Cidofovir, or Alovudine.
43. The composition of claim 34, wherein the antiviral drug is a reverse transcriptase inhibitor.
44. The composition of claim 43, wherein the reverse transcriptase inhibitor is Nevirapine, Delavirdine, Efavirenz, Etravirine, Etravirine, Rilpivirine, Adefovir dipivoxil, or Atevirdine.
45. The composition of claim 34, wherein the antiviral drug is a viral envelope fusion inhibitor.
46. The composition of claim 45, wherein the viral envelope fusion inhibitor is Docosanol, Enfuvirtide, or Maraviroc.
47. The composition of claim 34, wherein the antiviral drug is a prophylactic agent.
48. The composition of claim 47, wherein the prophylactic agent is a vaccine.
49. The composition of claim 48, wherein the prophylactic agent is RSV-IGIV, VZIG, or VariZIG.
50. The composition of claim 34, wherein the antiviral drug is a protein drug.
51. The composition of claim 50, wherein the protein drug is an antibody.
52. The composition of claim 34, wherein the antiviral drug is a proton transport inhibitor.
53. The composition of claim 52, wherein the proton transport inhibitor is Rimantadine or Methisazone.
54. The composition of claim 34, wherein the antiviral drug is a neuraminidase inhibitor.
55. The composition of claim 54, wherein the neuraminidase inhibitor is Zanamivir, Oseltamivir, Laninamivir octanoate, or Peramivir.
56. The composition of claim 33, wherein the cathepsin inhibitor is a cathepsin-B inhibitor, a cathepsin-L inhibitor; a cathepsin-S inhibitor; a cathepsin-F inhibitor; a cathepsin-X inhibitor; a cathepsin-K inhibitor; a cathepsin-V inhibitor; a cathepsin-W inhibitor; a cathepsin-C inhibitor; a cathepsin-0 inhibitor; a cathepsin-H inhibitor or a derivative thereof.
57. The composition of claim 33, wherein the cathepsin inhibitor is Balicatib (AAE581), E-64, E- 64a, E-64b, E-64c, E- 64d, CA-074, CA-074 Me,; CA-030,; CA-028, peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac-LVK-CHO, Z-Phe-Tyr-CHO, a epoxisuccinate Z-Phe-Tyr(0tBu)-C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp-CHO, Z-Phe-Leu- C0CH0.H20; peptidyl semicarbazone derivatives, peptidyl methylketone derivatives, peptidyl trifluoromethylketone, Biotin-Phe-Ala-fluoromethyl ketone, Z-Leu-Leu-Leu fluoromethyl ketone, Z-Phe-Phe-fluoromethyl ketone, N-Methoxysuccinyl-Phe-HOMO-Phe-fluoromethyl ketone, Z-Leu-Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone, peptidylchloromethases peptidylhydroxymates , peptidylhydroxylamines, peptidyl acyloxymethanes , peptidylacyloxymethyl ketones, peptidyl aziridines , peptidyl aryl vinylsufones , peptidyl arylvinylsulfonates, gallinamide analogs, peptidyl aldehydes , azepinone- based inhibitors , nitrile-containing inhibitors , thiosemicarbazone , propeptide mimics, thiocarbazate, oxocarbazate, azapaptides , peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ-Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala- CHN2, Z-Phe-Thr(OBzl)-CHN2, Z-Phe-Tyr (Ot-But)-CHN2, Z-Leu-Leu-Tyr-CHN2; peptidyl acyloxymethyl ketones; peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS; peptidyl nitriles; peptidyl disulfides, 5,5'-dithiobis[2-nitrobenzoic acid], cysteamines, 2,2'-dipyridyl disulfide; N-(4-Biphenylacetyl)-S-methyl cysteine-(D)-Arg-Phe-b phenethylamide; thiol alkylating agents, maleimides, azapeptides, azobenzenes, O-acylhydroxamates, Z-Phe-Gly-NHO- Bz, Z-FG-NHO-BzOME, lysosomotropic agents, chloroquine, ammonium chloride, Cystatins A, Cystatin B, Cystatin C, Cystatin D, Cystatins F, stefins, kininogens, Sialostain L, antimicrobial peptide LL-37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50, Odanacatib (MK-0822), , Relacatib (GSK-462795, SB-462795), SLV213 (K777 ORK1777), RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517, ONO-5334,MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY-106; VBY-285;VBY-825), VBY-129, SAR-114137, VBY- 891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV-247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI-1181181 (VTP-37948),VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY-210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP-0015962), SAR-164653, KGP94, VEL-0230, BLD2660 or a derivative thereof.
58. A method for prophylaxis or treatment of a disease, comprising administering to a subject in need thereof, the composition of any one of claims 32-57.
59. The method of claim 58, wherein the subject is a human patient.
60. The method of any one of claims 58-59, wherein the disease is a viral infection.
61. The method of claim 60, wherein the viral infection is caused by a Coronavirus, Orthomyxoviridae, influenza A virus, influenza B virus, influenza C virus, Thogotovirus, Dhori virus, infectious salmon anemia virus, Paramyxoviridae, parainfluenza virus, human respiratory syncytial virus (RSV), Sendai virus, Newcastle disease virus, mumps virus, rubeola (measles) virus, Hendra virus, Nipah virus, avian pneumovirus, canine distemper virus, Rhabdoviridae rabies virus, vesicular stomatitis virus (VSV), Mokola virus, Duvenhage virus, European bat virus, salmon infectious hematopoietic necrosis virus, viral hemorrhagic septicaemia virus, spring viremia of carp virus, snakehead rhabdovirus, Bomaviridae, Boma disease virus, Bunyaviridae Bunyamwera virus, Hantaan virus, Crimean Congo virus, California encephalitis virus, Rift Valley fever virus, sandfly fever virus, Arenaviridae Old World Arenaviruses, Lassa virus, Ippy virus, Lymphocytic choriomeningitis virus (LCMV), Mobala virus, Mopeia virus, New World Arenaviruses, Junin virus (Argentine hemorrhagic fever), Sabia (Brazilian hemorrhagic fever), Amapari virus, Flexal virus, Guanarito virus (Venezuela hemorrhagic fever), Machupo virus (Bolivian hemorrhagic fever), Latino virus, Boliveros virus, Parana virus, Pichinde virus, Pirital virus, Tacaribe virus, Tamiami virus, Whitewater Arroyo virus, arboviruses, togaviruses, Alphaviruses, Venezuela equine encephalitis virus, Sindbis virus, Rubivirus, Rubella virus, Chikungunya virus, Marburg viruses, Sudan virus, Flaviviridae, flavivirus, Pestivirus, and Hepacivirus, yellow fever virus, dengue fever virus, and Japanese encaphilitis (JE) virus, Pestivirus, Hepacivirus, hepatitis C virus, hepatitis C-like viruses, Japanese encephalitis Alfiiy, Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley encephalitis, St. Louis encephalitis, Stratford, Usutu, West Nile viruses, Pestivirus, bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV), border disease virus (BDV), Arenaviridae, Lymphocytic choriomeningitis virus (LCMV), Phlebovirus Rift valley fever virus, Hendra, Nipah, Riboviria, a rhinovirus, an enterovirus, a poliovirus, or an adenovirus.
62. The method of claim 61, wherein the viral infection is caused by a coronavirus.
63. The method of claim 62, wherein the coronavirus is SARS-CoV-2, SARS-CoV-1, or MERS- CoV.
64. A method for prophylaxis or treatment of a disease, comprising administering to a subject in need thereof, a cathepsin inhibitor, wherein the disease is caused by a coronavirus.
65. The method of claim 64, wherein the coronavirus is SARS-CoV-2, MERS-CoV, or SARS- CoV-1.
66. The method of any one of claims 64-65, wherein said cathepsin inhibitor is a cathepsin-B inhibitor; a cathepsin-L inhibitor; a cathepsin-S inhibitor; a cathepsin-F inhibitor; a cathepsin-X inhibitor; a cathepsin-K, inhibitor; a cathepsin-V inhibitor; a cathepsin-W inhibitor; a cathepsin- C inhibitor; or a cathepsin-0 inhibitor.
67. The method of any one of claims 64-66, wherein the cathepsin inhibitor is Balicatib, E-64, E- 64a, E-64b, E-64c, E- 64d, CA-074, CA-074 Me,; CA-030,; CA-028, peptidyl aldehyde derivatives leupeptin, antipain, chymostatin, Ac-LVK-CHO, Z-Phe-Tyr-CHO, a epoxisuccinate Z-Phe-Tyr(0tBu)-C0CH0.H20, 1-Naphthalenesulfonyl-Ile-Trp-CHO, Z-Phe-Leu- C0CH0.H20; peptidyl semicarbazone derivatives, peptidyl methylketone derivatives, peptidyl trifluoromethylketone, Biotin-Phe-Ala-fluoromethyl ketone, Z-Leu-Leu-Leu fluoromethyl ketone, Z-Phe-Phe-fluoromethyl ketone, N-Methoxysuccinyl-Phe-HOMO-Phe-fluoromethyl ketone, Z-Leu-Leu-Tyr-fluoromethyl ketone, Leupeptin trifluoroacetate, ketone, peptidylchloromethases peptidylhydroxymates , peptidylhydroxylamines, peptidyl acyloxymethanes , peptidylacyloxymethyl ketones, peptidyl aziridines , peptidyl aryl vinylsufones , peptidyl arylvinylsulfonates, gallinamide analogs, peptidyl aldehydes , azepinone- based inhibitors , nitrile-containing inhibitors , thiosemicarbazone , propeptide mimics, thiocarbazate, oxocarbazate, azapaptides , peptidyl halomethylketone derivatives, TLCK; bis(acylamino)ketone, 1,3- Bis(CBZ-Leu-NH)-2-propanone; peptidyl diazomethanes, Z-Phe-Ala- CHN2, Z-Phe-Thr(OBzl)-CHN2, Z-Phe-Tyr (Ot-But)-CHN2, Z-Leu-Leu-Tyr-CHN2; peptidyl acyloxymethyl ketones; peptidyl methylsulfonium salts; peptidyl vinyl sulfones, LHVS; peptidyl nitriles; peptidyl disulfides, 5,5'-dithiobis[2-nitrobenzoic acid], cysteamines, 2,2'-dipyridyl disulfide; N-(4-Biphenylacetyl)-S-methyl cysteine-(D)-Arg-Phe-b phenethylamide; thiol alkylating agents, maleimides, azapeptides, azobenzenes, O-acylhydroxamates, Z-Phe-Gly-NHO- Bz, Z-FG-NHO-BzOME, lysosomotropic agents, chloroquine, ammonium chloride, Cystatins A, Cystatin B, Cystatin C, Cystatin D, Cystatins F, stefins, kininogens, Sialostain L, antimicrobial peptide LL-37, Procathepsin B Fragment 26-50, Procathepsin B Fragment 36-50, Odanacatib (MK-0822), Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), SLV213 (K777 OR K1777), ,RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV-701, MIV-710, MIV-711, NC-2300, ORG-219517, ONO-5334,MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY-106; VBY-285;VBY-825), VBY- 129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV-247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI-1181181 (VTP- 37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY-210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP-0015962), SAR-164653, KGP94, VEL-0230, or BLD2660.
68. The method of any one of claims 64-67, wherein the viral infection is caused by a Orthomyxoviridae, influenza A virus, influenza B virus, influenza C virus, Thogotovirus, Dhori virus, infectious salmon anemia virus, Paramyxoviridae, parainfluenza virus, human respiratory syncytial virus (RSV), Sendai virus, Newcastle disease virus, mumps virus, rubeola (measles) virus, Hendra virus, Nipah virus, avian pneumovirus, canine distemper virus, Rhabdoviridae rabies virus, vesicular stomatitis virus (VSV), Mokola virus, Duvenhage virus, European bat virus, salmon infectious hematopoietic necrosis virus, viral hemorrhagic septicaemia virus, spring viremia of carp virus, snakehead rhabdovirus, Bomaviridae, Boma disease virus, Bunyaviridae Bunyamwera virus, Hantaan virus, Crimean Congo virus, California encephalitis virus, Rift Valley fever virus, sandfly fever virus, Arenaviridae Old World Arenaviruses, Lassa virus, Ippy virus, Lymphocytic choriomeningitis virus (LCMV), Mobala virus, Mopeia virus, New World Arenaviruses, Junin virus (Argentine hemorrhagic fever), Sabia (Brazilian hemorrhagic fever), Amapari virus, Flexal virus, Guanarito virus (Venezuela hemorrhagic fever), Machupo virus (Bolivian hemorrhagic fever), Latino virus, Boliveros virus, Parana virus, Pichinde virus, Pirital virus, Tacaribe virus, Tamiami virus, Whitewater Arroyo virus, arboviruses togaviruses, Alphaviruses, Venezuela equine encephalitis virus, Sindbis virus, Rubivirus, Rubella virus, Chikungunya virus, filoviruses, Marburg viruses, Sudan virus, Flaviviridae, flavivirus, Pestivirus, Hepacivirus, 25 yellow fever virus, dengue fever virus, and Japanese encaphilitis (JE) virus, Pestivirus, Hepacivirus, hepatitis C virus, hepatitis C-like viruses, Japanese encephalitis Alfiiy, Japanese encephalitis, Kokobera, Koutango, Kunjin, Murray Valley encephalitis, St. Louis encephalitis, Stratford, Usutu, West Nile viruses, Pestivirus, bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV), border disease virus (BDV), Arenaviridae, Phlebovirus Rift valley fever virus, Hendra, Nipah, Riboviria, coronaviruses, SARS-CoV-1, SARS-CoV-2, MERS-CoV, a rhinovirus, an enterovirus, a poliovirus, and an adenovirus.
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