WO1999038888A2 - Inhibiteurs peptidiques de l'activite de la serine protease associee a la proteine ns53 de vhc, leurs utilisations correspondantes et leur procede de production - Google Patents

Inhibiteurs peptidiques de l'activite de la serine protease associee a la proteine ns53 de vhc, leurs utilisations correspondantes et leur procede de production Download PDF

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WO1999038888A2
WO1999038888A2 PCT/IT1999/000022 IT9900022W WO9938888A2 WO 1999038888 A2 WO1999038888 A2 WO 1999038888A2 IT 9900022 W IT9900022 W IT 9900022W WO 9938888 A2 WO9938888 A2 WO 9938888A2
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Prior art keywords
hcv
acid
peptides
group
seq
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PCT/IT1999/000022
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English (en)
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WO1999038888A3 (fr
Inventor
Antonello Pessi
Christian STEINKÜHLER
Raffaele De Francesco
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Istituto Di Ricerche Di Biologia Molecolare
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Priority to AU25450/99A priority Critical patent/AU2545099A/en
Priority to CA002319306A priority patent/CA2319306A1/fr
Priority to JP2000529354A priority patent/JP2002509075A/ja
Priority to EP99905173A priority patent/EP1053249A2/fr
Publication of WO1999038888A2 publication Critical patent/WO1999038888A2/fr
Publication of WO1999038888A3 publication Critical patent/WO1999038888A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/24011—Flaviviridae
    • C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
    • C12N2770/24222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to the molecular biology and to the virology of the human hepatitis C virus (HCV) .
  • HCV human hepatitis C virus
  • it relates to the research of molecules that could potentially be adopted in the therapy of the variety of hepatitis consequent to the infection of this virus.
  • the method most frequently adopted in art in order to generate molecules with therapeutical potentialities towards viral pathologies is that of subjecting collections of compounds, containing a large number of single chemical entities of high molecular diversity, to an automatized program to detect the existence of single active agents. Those agents are then subjected to further chemical modifications aimed at improving their therapeutical potential.
  • the HCV virus is the principal etiologic agent of non-A non-B hepatitis (NANB) , whose chronic infection in serum is often a cause of liver cirrhosis and may progress in 20 - 30 years time to hepatocellular carcinoma.
  • NANB non-A non-B hepatitis
  • it is a "virus with a membrane, containing an encapsidized RNA+ genoma of approximately 9.4 Kb.
  • the geno ic organisation of the HCV virus comprises a structural region, coding for proteins concurring to form the virus structure, and a non-structural region NS, coding for functional proteins (helicase/protease; RNA- dependant RNA polymerase) .
  • Both regions are placed in a single open reading frame (ORF) variable between 9030 and 9099 nucleotides that is translated in a single viral polyprotein, whose length may vary between 3010 and 3033 amino acids, only afterwards, during the viral infection cycle, proteolytically processed in individual genie products.
  • ORF open reading frame
  • the processing of the nonstructural portion of the HCV polyprotein is due to the activity of two different proteases, on of which is a serine-protease contained inside of the N-terminal region (amino acids 1-181) of the NS3 protein (therefore named NS3 protease) , responsible of the cleaving at NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B sites (Bartenschlager, R. An tiviral Chemistry & Chemotherapy 1997) .
  • NS3 is a 68 KDa protein, in fact showing 2 functional domains, one serine protease domain in the first 200 amino-terminal amino acids and a RNA-dependant ATPase domain at the carboxy- terminus.
  • the subject of the present invention are peptides capable of inhibiting protease activity associated to the HCV NS3 enzyme. They have been identified during studies on NS3 enzyme substrate specificity, due to the identification among products of NS3 proteolytic action on the viral polyprotein, of some peptides capable of acting as inhibitors of the protease itself.
  • proteolysis- derived peptides bearing in the C-terminal portion of their sequence the amino acids naturally occurring in P4, P3, P2 and PI positions (according to the definition of Schechter, I. and Berger, A., 1967) of the junction sites NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B, exhibit an inhibitory capacity towards the NS3 protease itself.
  • the sequences of the abovementioned four cleaving sites of the NS3 enzyme are listed in table I. TABLE I: Sequence of the NS3 cleaving sites
  • sequence thereof corresponds to the P6-P1 residues respectively of sites NS4A/NS4B and NS5A/NS5B.
  • inhibitory capability can be specifically ascribed to the presence of at least a free acid function in the C-terminal position of such peptides .
  • the amino acids in the other positions of the peptides although significantly affecting the level of inhibitory capability of the peptides, can not by themselves confer inhibitory properties to the same peptides .
  • the sequence of the peptides of viral origin corresponds to the P6-P1 residues of the viral sites, which they are derived from
  • the positions occupied by each amino acid residue in all the peptides obtained have been conventionally denominated from P6 to PI, P6 being the the position of the N-terminal end and PI being the position of the C-terminal end.
  • subject of the present invention is first of all peptides consisting in six amino acid residues arranged in positions from P6 to PI, P6 being the position of the N-terminal end and PI being the position of the C-terminal end, characterized in that the amino acid in the PI position has at least a free acid function and in that they are capable of inhibiting the protease activity of the HCV virus associated to the NS3 protein.
  • the peptides wherein the amino acid in PI position is a cysteine, an analog or a derivative thereof, and in particular an amino acid selected from the group comprising L-cysteine, D-cysteine, homocysteine, S-methylcysteine, alanine, S- ethylcysteine, threonine, methionine, serine and penicillamine;
  • the above mentioned peptides having in P5 position an acid function, in particular selected from the group comprising aspartic acid, succinic acid, acylsulfonamide;
  • the above mentioned peptides having in the P4 position an hydrophobic amino acid in particular selected from the group comprising 3, 3 , diphenilalanine, leucine, isoleucine and phenylglicine; the above mentioned peptides having in the position P3 an amino acid selected from the group comprising glutamic acid, valine and isoleucine, and in a realization form having in the position P5 an amino acid selected from the group comprising aspartic acid, p-nitrophenylalanine, tyrosine, g-carboxyglutamic acid, D-phenylalanine, D-tyrosine, D-valine, D-isoleucine, D- 3, 3-diphenylalanine, D-aspartic acid, D-glutamic acid and D-g-carboxyglutamic acid, in another realization form, together with such amino acid in P5 position or not, in the position PI an amino acid selected from the group comprising aminobutyric acid, norvaline and valine
  • Cases of particular relevance are the one wherein the peptides are capable of inhibiting 50% of the NS3 enzymatic activity at a concentration lower than or equal to 2 ⁇ M (IC 5 o) , and the one wherein the peptides have in the positions P4, P3, P2 and PI, the amino acids naturally occurring respectively in P4, P3, P2 and PI positions of one of the junction sites of the HCV virus, said junction sites being selected from the group comprising NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B.
  • peptides obtainable by the proteolysis reaction of polipeptides containing at least one of the junction sites of the polyprotein of said HCV virus, said junction sites being selected from the group consisting of NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B junction sites .
  • junction sites consist of decapeptides, containing the amino acids naturally occurring in the positions P4, P3, P2 and PI of NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B junction sites;
  • the HCV viruses is selected from the group comprising HCV virus of la, lb, lc, 2a, 2b, 2c, 2d, 2e, 2f, 3a, 3b, 3c, 3d, 3e, 3f, 4a, 4b, 4c, 4d, 5a, 5a, 6b, 7a, 7b, 7c, 7d, 8a, 8b, 9a, 9b, 9c, 10a and 11a genotype, described as non- limiting examples in Tokita, M.
  • the peptides according to the present invention are those having an amino acid sequence selected from the group comprising the sequences reported in the annexed sequence listing as from SEQ ID NO:l to SEQ ID NO: 69.
  • a further subject of the present invention is the use of the abovementioned peptides for derivation of binding or inhibition assays of the enzymatic activity of HCV NS3 protease, but above all the utilisation of those peptides for the preparation of drugs for the treatment of non-A non-B hepatitis .
  • peptide inhibitors in the "co- crystallisation" with the enzyme, to obtain structural information on the enzyme active site , thereby facilitating the discovery of new enzymatic activity modulators, of peptidic nature or not.
  • All peptides as described above can be used to prepare pharmaceutical compositions, characterised in that they comprise beside at least one of the aforedescribed peptides, a pharmaceutically effective carrier, vehicle or auxiliary agent, as well as compositions that likewise comprise at least one of said peptides .
  • a further subject of the present invention is a process for the production of at least one of the afore mentioned peptide characterized by the step of carrying out the the proteolysis of polypeptides containing at least one among the sequences of the NS3/NS4A, NS4A/NS4B, NS4B/NS5A and/or NS5A/NS5B junction sites of the polyprotein of HCV virus.
  • HCV displays a genotype la, lb, lc, 2a, 2b, 2c, 2d, 2e, 2f, 3a, 3b, 3c, 3d, 3e, 3f, 4a, 4b, 4c, 4d, 5a, 5a, 6b, 7a, 7b, 7c, 7d, 8a, 8b, 9a, 9b, 9c, 10a and/or 11a, described as non-limiting examples in Tokita, M. et al J. of Gen. Virol. 1996; and in Myakawa, Y., et al, Molecular Med.
  • the virus is of H-FDA, H-AP, HCV-1, HCV-J, HCV-BK, HC-J6, HCV-T, HC-J8, HCV-JT and/or HCV-JT' strain described as non-limiting examples in Grakou et al, J. of Virol., 1993.
  • junction sites contained in the NS3 polypeptide substrate, consist of decapeptides, containing the amino acids naturally occurring in P4, P3, P2 and PI positions of the same junction sites themselves .
  • the invention will be better understood with the aid of the annexed figures.
  • Figure 1 shows the reaction kinetics of the NS4A/NS4B substrate cleaving catalysed by NS3 protease.
  • Figure 2 shows the determination of the IC5 0 of peptide SEQ ID NO:l by displacement of the fluorescent marker derived from peptide SEQ ID NO: 69.
  • fig. 2a the intensity decrease of the fluorescence spectrum of the NS3 protease-peptide complex SEQ ID NO: 69 is plotted against the increasing concentration of the peptide SEQ ID NO: 1.
  • fig. 2b the variation of intensity of the fluorescence spectrum at 520nm is plotted against the peptide SEQ ID NO: 1 concentration for the IC50 assessment.
  • the subject of the present invention are peptides having a relevant inhibitory capacity towards of the NS3-associated protease activity, some of which correspond to those of viral origin, others thereby obtained by modifications of one or more amino acid residues.
  • Alg allylglycine
  • CysAs Cys presenting in C-terminal position an acylsulfonamide
  • Gla g-carboxyglutamic acid
  • GluS Glu whereto a succinyl group is bound
  • MeGlu N-methyl-glutamic aci ⁇
  • MeGly methyl-glycine
  • SEQ ID NO: 32 was taken in turn as a starting point to optimise the P3 position.
  • the result was obtained systematically by synthesising a series of analogs that, though presenting the same structure of the. SEQ ID NO: 32, were modified in P3 position only.
  • SEQ ID NO: 32 was again taken as a starting point to optimise P3 position. As for P3 and P4 positions, the result was obtained systematically by the synthesis of a series of analogs that, though presenting the same structure of the SEQ ID NO:32, were modified in P5 position only.
  • P5 p-nitrophenylalanine
  • P5 tyrosine
  • SEQ ID NO:59, IC50 0.135 ⁇ M
  • P5 D-g- carboxy
  • D-cysteine for L-cysteine exchange is highly detrimental of the inhibitory capacity in the more potent analogs modified in P2 and P4 positions
  • N-methyla ted Peptidomimetics deri ved from SEQ ID NO: l and SEQ ID NO: 8
  • Escherichia coli BL21 (DE3) cells were transformed with a plasmid containing the cDNA coding for the serine protease domain of the HCV BK strain NS3 protein (amino acids 1-180) under the control of bacteriophage T7 gene 10 promoter.
  • the protease domain was purified as previously described (Steinkuhier, C. et al . , J. Biol . Chem . 1996) .
  • the enzyme was homogenous as assessed with electrophoresis on polyacrylamide gel in presence of sodium dodecyl sulphate (SDS-PAGE) using as detector the silver stain, and over 95% pure as assessed from reversed phase HPLC carried out using a 4.6 x 250 mm Vydac C4 column.
  • Enzyme preparations were routinely checked by mass spectrometry done on HPLC purified samples, using a Perkin Elmer API 100 instrument, and N- terminal sequence analysis carried out using Edman degradation on an Applied Biosystems model 470A gas- phase sequencer. Both techniques indicated that in more than 90% of the enzyme molecules the N-terminus methionine and alanine have been removed, yielding an enzyme starting with proline in position 2.
  • Enzyme stocks were quantitated by quantitative analysis of the amino acidic content, shock-frozen in liquid nitrogen and kept in aliquots at -80°C until use. Control experiments have proved that this freezing procedure does not interfere with the specific activity of the enzyme.
  • Peptide synthesis was performed by Fmoc chemistry (Phluorenhylmethyl-oxycarbonyl) /t-Bu ( tert- buthyl) chemistry , essentially as described in Atherton and Sheppard. (19-89) .
  • Peptides were assembled on a Novasyn® TGA (Novabiochem) resin and cleaved off the polymer at the end of the synthesis with TFA 88%, phenol 5%, triisopropylsilane 2%, water 5% (Sole, N. A. and Barany, G. J. Org. Chem . 1992) .
  • Crude peptides were purified by reversed-phase HPLC on a Nucleosyl C18, 250 x 21 mm, 100 A, 7 ⁇ m using water, 0.1% TFA and acetonitrile 0.1% TFA as eluents .
  • Analytical HPLC was performed on Ultrasphere C18, 250 x 4.6 mm, 80 A, 5 ⁇ m (Beckman) .
  • Purified peptides were characterised by mass spectrometry, [ H] -NMR and amino acid analysis.
  • HPLC protease a ctivi ty assay Concentration on stock solutions of peptides, prepared in DMSO or in buffered aqueous solution and kept at -80°C until use, was determined by quantitative amino acid analysis performed on azeotropic HC1- hydrolysed samples. If not differently specified, cleaving assay was performed in 57 ⁇ l 50 mM Tris pH 7.5, 2% CHAPS, 50% glycerol, 10 mM in DTT (buffer A), to which 3 ⁇ l of the substrate peptide Ac- DEMEECASHLPYK(Ac) -NH2 were additioned.
  • Pep4AK As protease co- factor a peptide spanning the central hydrophobic core (residues 21-34) was used of the NS4A protein, with a three-lysine tag at the N-terminus to increase solubility (Bianchi, E. et al . , Biochemistry 1997), Pep4AK (KKKGSVVIVGRIILSGR-NH2) . PeP4AK was pre-incubated for 10 minutes with 10-50 nM protease prior to the addition of the substrate. Incubation time was chosen in order to obtain a substrate conversion of less than 7%.
  • Cleaving products were quantitated by integration of chromatograms with respect to appropriate standards. Initial rates of cleaving were determined on samples characterized by a substrate conversion rate of less than 7%. Kinetic parameters were calculated from the initial rates as a function of substrate concentration with the help of Kaleidograph® software, assuming Michaelis-Menten kinetics.
  • the HCV-protease J strain was stored until use at -80°C in 250 mM NaCl, phosphate buffer pH 6.5, 50% glycerol, 0.1% CHAPS; PeP4AK was stored at -80°C in DMSO; the tritiated substrate Ac-DEMEECASHLPYK ( 3 H-Ac)- NH 2 and the corresponding cold substrate Ac- DEMEECASHLPYK(Ac)-NH2 were stored at -80 °C in DMSO/DTT.
  • the assay was run in Costar polypropilene 96-well plates.
  • the composition of the reaction mixture was as follows (100 ⁇ l) :
  • reaction mixture was diluted in DMSO (final concentration 10% DMSO)
  • PeP4AK was pre-incubated with protease for 5 min prior to addition of substrate mix. In these conditions, the substrate Km was 7 ⁇ 2 ⁇ M. Plates were shaken for 30 minutes at room temperature, then a ionic exchange resin (100 ⁇ l of 20% Fractogel TSK-DEAE® 650S, Merck) was added to capture unprocessed substrate and plates shaken for another 10 minutes. After allowing the resin to settle by gravity, 30 ⁇ l of the reaction mix were transferred in a 96-well plate (Picoplate, Packard) , admixed with 250 ⁇ l of scintillation cocktail Microscint 40, and the radioactivity measured in a scintillation Packard Top Count ⁇ -counter.
  • a ionic exchange resin 100 ⁇ l of 20% Fractogel TSK-DEAE® 650S, Merck
  • Peptides binding NS3 active site containing radioisotopes can be adopted to find other compounds binding the same site using techniques known in art. For instance, a peptide having a sequence that binds to NS3 protease active site marked using the abovedescribed techniques can be added to buffered solution containing NS3 protease or NS3 protease and its cofactor NS4A, or peptides deriving from the sequence of this cofactor.
  • the protease bound to the peptide can be isolated using filtration techniques, chromatographic resins bonding, or precipitation using saline solutions or organic reagents.
  • the amount of marked peptide can easily be determined using detecting techniques of the radioactive decay process as scintillation. In this process, the addition of a substance capable of binding to the NS3 active site prior to protease isolation using said techniques, entails the displacing of the marked peptide and therefore a reduction in the emission of the radioactive decay products.
  • the phenomenon of resonance energy transfer decays with the sixth power of the distance and is operative at distances of between 10 and 100 A, making it extremely sensitive to determine the bond between two molecules .
  • the molecule in SEQ ID NO: 69 is a hesapeptide derived by the optimization of the sequence of a NS3 protease cleaving product, SEQ ID NO: 23, wherein the methionine residue was replaced with an 2,3- diaminopropionic acid residue, derivatized on P3 amino group with the dansyl group.
  • the SEQ ID NO: 69 molecule can be utilised to determine the binding of other molecules to NS3 protease active site, capable therefore of displacing it from the interaction with- the enzyme.
  • a typical experiment is shown in Fig. 2.
  • SEQ ID NO: 69 200 nM To a buffered solution containing NS3 protease 200 nM complexed with Pep4AK were added SEQ ID NO: 69 200 nM. The bond of the two molecules was measured exciting NS3 tryptophans at a 280 nm wavelength and recording emission spectrum around 520 nm.
  • HPLC high-performance liquid chromatography
  • TFA Trifluoroacetic acid

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Abstract

L'invention concerne des peptides capables d'inhiber l'activité de la sérine protéase associée à la protéine NS53 du virus de l'hépatite C (VHC), leurs utilisations et leur procédé de production consistant à effectuer la protéolyse de polypeptides contenant au moins une séquence sélectionnée parmi les sites de jonction NS3/NS4A, NS4A/NS4B, NS4B/NS5A et/ou NS5A/NS5B de la polyprotéine du VHC.
PCT/IT1999/000022 1998-02-02 1999-02-02 Inhibiteurs peptidiques de l'activite de la serine protease associee a la proteine ns53 de vhc, leurs utilisations correspondantes et leur procede de production WO1999038888A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU25450/99A AU2545099A (en) 1998-02-02 1999-02-02 Peptide inhibitors of the serine protease activity associated to the ns3 proteinof hcv, relevant uses and process of production
CA002319306A CA2319306A1 (fr) 1998-02-02 1999-02-02 Inhibiteurs peptidiques de l'activite de la serine protease associee a la proteine ns53 de vhc, leurs utilisations correspondantes et leur procede de production
JP2000529354A JP2002509075A (ja) 1998-02-02 1999-02-02 Ｈｃｖのｎｓ３タンパク質に関連したセリンプロテアーゼ活性のペプチド阻害剤、関連する使用およびその製造方法
EP99905173A EP1053249A2 (fr) 1998-02-02 1999-02-02 Inhibiteurs peptidiques de l'activite de la serine protease associee a la proteine ns53 de vhc, leurs utilisations correspondantes et leur procede de production

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT98RM000061A IT1299134B1 (it) 1998-02-02 1998-02-02 Procedimento per la produzione di peptidi con proprieta' inibitrici della proteasi ns3 del virus hcv, peptidi cosi' ottenibili e peptidi
ITRM98A000061 1998-02-02

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WO1999038888A2 true WO1999038888A2 (fr) 1999-08-05
WO1999038888A3 WO1999038888A3 (fr) 1999-10-07

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JP (1) JP2002509075A (fr)
AU (1) AU2545099A (fr)
CA (1) CA2319306A1 (fr)
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WO (1) WO1999038888A2 (fr)

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WO2001032691A1 (fr) * 1999-11-02 2001-05-10 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Inhibiteurs de protease ns3 hcv
WO2002057425A2 (fr) 2001-01-22 2002-07-25 Merck & Co., Inc. Derives de nucleoside comme inhibiteurs de l'arn polymerase virale arn-dependante
US6608027B1 (en) 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
US6642204B2 (en) 2002-02-01 2003-11-04 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
US6869964B2 (en) 2002-05-20 2005-03-22 Bristol-Myers Squibb Company Heterocyclicsulfonamide hepatitis C virus inhibitors
US6878722B2 (en) 2002-05-20 2005-04-12 Bristol-Myers Squibb Company Substituted cycloalkyl P1′ hepatitis C virus inhibitors
WO2005037214A2 (fr) 2003-10-14 2005-04-28 Intermune, Inc. Acylsulfonamides et acides carboxyliques macrocycliques utilises en tant qu'inhibiteurs de la replication du virus de l'hepatite c
WO2005123087A2 (fr) 2004-06-15 2005-12-29 Merck & Co., Inc. Analogues nucleosidiques de c-purine, servant d'inhibiteurs d'arn-polymerase virale arn-dependante
WO2006012078A2 (fr) 2004-06-24 2006-02-02 Merck & Co., Inc. Phosphoramidates d'aryle nucleosidiques pour le traitement d'infection virale arn dependante de l'arn
US6995174B2 (en) 2002-05-20 2006-02-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7041698B2 (en) 2002-05-20 2006-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7091184B2 (en) 2002-02-01 2006-08-15 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
WO2006021896A3 (fr) * 2004-08-27 2006-08-17 Tripep Ab Modele de souris transgenique du virus de l'hepatite c (hcv) et identification de therapeutiques du hcv
US7119072B2 (en) 2002-01-30 2006-10-10 Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the hepatitis C virus
WO2006109196A2 (fr) * 2005-02-04 2006-10-19 Tripep Ab Modeles de souris transgeniques du virus de l'hepatite c (vhc) et identification des therapies pour le vhc
US7132504B2 (en) 2003-11-12 2006-11-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7135462B2 (en) 2003-11-20 2006-11-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2007015855A1 (fr) 2005-07-20 2007-02-08 Merck & Co., Inc. Inhibiteurs de la protease ns3 du vhc
WO2007021610A2 (fr) 2005-08-09 2007-02-22 Merck & Co., Inc. Derives d'acetaux cycliques de ribonucleosides pour traiter une infection virale d'arn arn dependante
WO2007044893A2 (fr) 2005-10-11 2007-04-19 Intermune, Inc. Composés et méthodes pour l'inhibition de la réplication du virus de l'hépatite c
WO2007059221A2 (fr) 2005-11-11 2007-05-24 Vertex Pharmaceuticals, Inc Variantes du virus de l'hepatite c
US7273885B2 (en) 2002-04-11 2007-09-25 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
US7309708B2 (en) 2003-11-20 2007-12-18 Birstol-Myers Squibb Company Hepatitis C virus inhibitors
EP1944042A1 (fr) 2003-10-27 2008-07-16 Vertex Pharmceuticals Incorporated Combinaisons pour le traitement HCV
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
WO2009033659A1 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Inhibiteur de protéase du vhc et octréotide en tant qu'agents thérapeutiques
US7511157B2 (en) 2004-07-20 2009-03-31 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor dipeptide analogs
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
EP2103623A2 (fr) 2005-07-25 2009-09-23 Intermune, Inc. Nouveaux inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7696242B2 (en) 2004-07-20 2010-04-13 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor peptide analogs
US7705138B2 (en) 2005-11-11 2010-04-27 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
EP2194043A2 (fr) 2005-08-19 2010-06-09 Vertex Pharmceuticals Incorporated Procédés et intermédiaires
US7745444B2 (en) 2003-09-05 2010-06-29 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
US7749961B2 (en) 2004-01-21 2010-07-06 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
WO2010082050A1 (fr) 2009-01-16 2010-07-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Composés benzoxazocines substitués 7-aminoalkyle macrocycycliques destinés au traitement des infections par hépatite c
WO2010084115A2 (fr) 2009-01-20 2010-07-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Agents antiviraux
US7767660B2 (en) 2006-12-20 2010-08-03 Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
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US7989438B2 (en) 2007-07-17 2011-08-02 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Therapeutic compounds
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EP2364984A1 (fr) 2005-08-26 2011-09-14 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases,
EP2399988A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Système de culture cellulaire pour la réplication du virus de l'hépatite C par l'activation ou l'inhibition de récepteur farnésoïde X (FXR) et méthode de diagnostic pour l'infection avec VHC
US8101595B2 (en) 2006-12-20 2012-01-24 Istituto di Ricerche di Biologia Molecolare P. Angletti SpA Antiviral indoles
US8138164B2 (en) 2006-10-24 2012-03-20 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8178491B2 (en) 2007-06-29 2012-05-15 Gilead Sciences, Inc. Antiviral compounds
US8178520B2 (en) 2006-05-15 2012-05-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Macrocyclic compounds as antiviral agents
US8183216B2 (en) 2007-09-24 2012-05-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Nucleoside derivatives as inhibitors of viral polymerases
US8187874B2 (en) 2003-10-27 2012-05-29 Vertex Pharmaceuticals Incorporated Drug discovery method
WO2012107589A1 (fr) 2011-02-11 2012-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement et la prévention des infections à vhc
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8278322B2 (en) 2005-08-01 2012-10-02 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8309540B2 (en) 2006-10-24 2012-11-13 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8314062B2 (en) 2006-06-23 2012-11-20 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic compounds as antiviral agents
US8377873B2 (en) 2006-10-24 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8377874B2 (en) 2006-10-27 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8399615B2 (en) 2005-08-19 2013-03-19 Vertex Pharmaceuticals Incorporated Processes and intermediates
WO2013074386A2 (fr) 2011-11-15 2013-05-23 Merck Sharp & Dohme Corp. Inhibiteurs de la protéase ns3 du vhc
US8461107B2 (en) 2008-04-28 2013-06-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
WO2013106344A1 (fr) 2012-01-12 2013-07-18 Ligand Pharmaceuticals, Inc. Nucléosides 2'-c-méthyl comprenant un diester de phosphate cyclique de 1,3-propanediol (2-oxo-[1,3,2]-dioxaphosphorinane à la position 5'
US8513186B2 (en) 2007-06-29 2013-08-20 Gilead Sciences, Inc. Antiviral compounds
WO2014123795A2 (fr) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
WO2014123794A1 (fr) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
US8927569B2 (en) 2007-07-19 2015-01-06 Merck Sharp & Dohme Corp. Macrocyclic compounds as antiviral agents
US9738661B2 (en) 2006-10-27 2017-08-22 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008304A2 (fr) * 1995-08-22 1997-03-06 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Methode de production, de purification et d'analyse de polypeptides par l'activite proteolytique de la vhc ns3 protease
WO1997043310A1 (fr) * 1996-05-10 1997-11-20 Schering Corporation Inhibiteurs synthetiques de la protease ns3 du virus de l'hepatite c
WO1999007733A2 (fr) * 1997-08-11 1999-02-18 Boehringer Ingelheim (Canada) Ltd. Peptides inhibiteurs de l'hepatite c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008304A2 (fr) * 1995-08-22 1997-03-06 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Methode de production, de purification et d'analyse de polypeptides par l'activite proteolytique de la vhc ns3 protease
WO1997043310A1 (fr) * 1996-05-10 1997-11-20 Schering Corporation Inhibiteurs synthetiques de la protease ns3 du virus de l'hepatite c
WO1999007733A2 (fr) * 1997-08-11 1999-02-18 Boehringer Ingelheim (Canada) Ltd. Peptides inhibiteurs de l'hepatite c

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GRAKOUI E.A.: "Characterization of the HCV-encoded serine proteinase" J.VIROL., vol. 67, no. 5, 1993, pages 2832-2843, XP002111520 cited in the application *
INGALLINELLA E A: "Potent peptide inhibitors of human HCV NS3 protease are obtained by optimizing the cleavage products" BIOCHEMISTRY, vol. 37, 23 June 1998 (1998-06-23), pages 8906-8914, XP002086572 ISSN: 0006-2960 *
LANDRO E.A.: "Mechanistic role of an NS4A cofactor with the truncated NS3 protease of HCV" BIOCHEMISTRY, vol. 36, no. 31, 1997, pages 9340-9348, XP002111518 EASTON, PA US *
LLINAS-BRUNET M ET AL: "Peptide-based inhibitors of the hepatitis C virus serine protease" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 8, no. 13, 7 July 1998 (1998-07-07), page 1713-1718 XP004137115 ISSN: 0960-894X *
TOKITA E.A.: "HCV variants from Jakarta, Indonesia classifiable into novel genotypes in the second (2e and 2f) and eleventh (11a) genetic groups." J.GEN.VIROL., vol. 77, 1996, pages 293-301, XP002111519 cited in the application *

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