WO2021151391A1 - Application du composé isovalérylspiramycine et sa composition pour la préparation d'un médicament antiviral - Google Patents

Application du composé isovalérylspiramycine et sa composition pour la préparation d'un médicament antiviral Download PDF

Info

Publication number
WO2021151391A1
WO2021151391A1 PCT/CN2021/074401 CN2021074401W WO2021151391A1 WO 2021151391 A1 WO2021151391 A1 WO 2021151391A1 CN 2021074401 W CN2021074401 W CN 2021074401W WO 2021151391 A1 WO2021151391 A1 WO 2021151391A1
Authority
WO
WIPO (PCT)
Prior art keywords
isovalerylspiramycin
virus
iii
influenza
enterovirus
Prior art date
Application number
PCT/CN2021/074401
Other languages
English (en)
Chinese (zh)
Inventor
姜恩鸿
夏明钰
赵小峰
姜洋
Original Assignee
沈阳福洋医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 沈阳福洋医药科技有限公司 filed Critical 沈阳福洋医药科技有限公司
Publication of WO2021151391A1 publication Critical patent/WO2021151391A1/fr

Links

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of antibiotics, and specifically relates to the application of isovalerylspiramycin compounds and their compositions in the preparation of antiviral drugs.
  • Viral infection refers to the process by which viruses invade the body through multiple channels and multiply in susceptible host cells. Viruses can only reproduce in cells, relying entirely on the body's cells to provide synthesis and energy, and have strict cell parasitic properties. Virus infection has caused great harm to human life and health.
  • Enterovirus particles are small, octahedral, with a diameter of 24-30nm, no lipids, single-stranded ribonucleic acid in the core, resistance to ether and other lipid solvents, acid resistance, and resistance to various antibiotics, antiviral drugs, and detergents. Resistance. Enteroviruses include polio virus, Coxsackie virus, and orphan virus (ECHO virus) that causes cytopathic effects in the human intestinal tract. Enteroviruses discovered after the 67 types of the three named enteroviruses mentioned above are all named according to their ordinal numbers, that is, enterovirus types 68, 69, 70, 71, 72, etc. Enterovirus is an infectious disease caused by a virus.
  • Herpes viruses are viruses with an envelope and a double-stranded DNA genome. At present, more than 100 kinds have been discovered, which can be divided into three categories (subfamily) of ⁇ , ⁇ , and ⁇ . It has a wide range of infection hosts, mainly affecting the skin, mucous membranes and nerve tissues, and seriously affecting the health of humans and other animals.
  • Influenza virus is abbreviated as influenza virus and is divided into three types: A (A), B (B), and C (C). Influenza viruses discovered in recent years will be classified as D (D). Among them, the antigenicity of influenza A virus is prone to mutate, causing many worldwide pandemics. Influenza B virus is also relatively pathogenic to humans, but people have not found that influenza B virus has caused a worldwide pandemic; influenza C virus only causes unobvious or mild upper respiratory tract infections in humans, and rarely causes epidemics . The typical clinical symptoms of these diseases are acute high fever, general pain, significant fatigue and respiratory symptoms. Influenza viruses are mainly spread through droplets in the air, contact between susceptible and infected persons, or contact with contaminated items.
  • Human immunodeficiency virus also known as HIV, is a retrovirus that causes defects in the human immune system. This virus will attack and gradually destroy the human immune system, leaving the host unprotected when infected. People who are infected with human immunodeficiency virus and die often die from secondary infections or cancer. AIDS is the final stage of human immunodeficiency virus infection.
  • enterovirus Whether it is enterovirus, herpes virus, influenza virus, or HIV, it is necessary to develop more effective methods to inhibit viral infection and protect human life, health and safety.
  • Carrimycin (Carrimycin), also known as Bitespiramycin and Shengjimycin, was developed by the Institute of Biotechnology of the Chinese Academy of Medical Sciences in cooperation with the applicant.
  • the 4" isovaleryl transferase group (4"-o-acyl-transferase) was cloned into the spiramycin producing bacteria, and the spiramycin 4"-OH was acylated and the isovaleryl side chain was added at the 4" position
  • Calinomycin is composed of a variety of spiramycin derivatives, the total content of the main active ingredient isovalerylspiramycin (I+II+III) is not less than 60%, and the total content of acylated spiramycin is not less than 80% is an acceptable pharmaceutical composition in pharmacy.
  • the central structure is a 16-membered lactone ring, which is connected with one molecule of folofamine, one molecule of mycosaminoglycan and one molecule of mycaminophen.
  • the composition standard is isovalerylspiramycin III ⁇ 30%, the total proportion of isovalerylspiramycin I, II, III ⁇ 60%, the proportion of total acylated spiramycin ⁇ 80%, and the sum of other unknown components ⁇ 5%.
  • isovalerylspiramycin compound and its composition can inhibit influenza virus, enterovirus, herpes virus and AIDS virus in the existing prior art.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide an application of isovalerylspiramycin compound and its composition in the preparation of antiviral drugs, especially in the preparation of anti-enteric virus and herpes virus , Influenza virus, HIV infection drugs.
  • the first object of the present invention is to provide the use of isovalerylspiramycin compounds, or pharmaceutically acceptable salts thereof, or combinations thereof in the preparation of drugs for the treatment or prevention of enterovirus infections.
  • the enterovirus includes enterovirus type 68, enterovirus type 69, enterovirus type 70, enterovirus type 71 or enterovirus type 72;
  • the enterovirus is enterovirus 71.
  • the medicine for treating or preventing enterovirus infection includes a first active ingredient of the medicine and a second active ingredient of the medicine, and the first active ingredient of the medicine includes colimycin, isovalerylspiramycin I, and isovalerylspiramycin I.
  • the first active ingredient of the medicine includes colimycin, isovalerylspiramycin I, and isovalerylspiramycin I.
  • the second active ingredient of the drug is selected from antiviral drugs and immunity enhancing drugs.
  • the first active ingredient of the medicine and the second active ingredient of the medicine can be a separate preparation, or can be compounded into one preparation.
  • the second object of the present invention is to provide the use of isovalerylspiramycin compounds, or pharmaceutically acceptable salts thereof, or combinations thereof in the preparation of medicines for the treatment of herpes virus infections.
  • Further schemes include one of colimycin, isovalerylspiramycin I, isovalerylspiramycin II, isovalerylspiramycin III, or isovalerylspiramycin I, isovalerylspiramycin I Application of a combination of two or three kinds of Iovalerylspiramycin III in the preparation of medicines for the treatment or prevention of herpes virus infection;
  • the herpes virus includes herpes simplex virus type 1 (herpes simplex virus-1, HSV-1), herpes simplex virus type 2 (herpes simplex virus-2, HSV-2), and varicella-zoster virus (varicella).
  • herpes simplex virus type 1 herpes simplex virus-1, HSV-1
  • herpes simplex virus type 2 herpes simplex virus-2, HSV-2
  • varicella-zoster virus varicella-zoster virus
  • VZV herpes simplex virus
  • EBV Epstein-Barr virus
  • HCMV human cytomegalovirus
  • HHV-6 human herpes virus type 6
  • HHV-7 human herpes virus type 7
  • the herpes virus is herpes simplex virus type 1.
  • the drug for treating herpes virus infection includes a first active drug ingredient and a second active drug ingredient, and the first active drug ingredient includes colimycin, isovalerylspiramycin I, and isovaleryl helix One of Iovalerylspiramycin II, isovalerylspiramycin III, or a combination of two or three of isovalerylspiramycin I, isovalerylspiramycin II, and isovalerylspiramycin III;
  • the active ingredients of the two drugs are selected from antiviral drugs and immunity enhancing drugs.
  • the first active ingredient of the medicine and the second active ingredient of the medicine can be a separate preparation, or can be compounded into one preparation.
  • the third object of the present invention is to provide the use of isovalerylspiramycin compounds, or pharmaceutically acceptable salts thereof, or combinations thereof in the preparation of drugs for the treatment or prevention of influenza virus infection.
  • influenza virus includes influenza A virus, influenza B virus, influenza C virus or a combination thereof;
  • influenza virus is influenza A virus
  • influenza virus is A H1N1 influenza virus, A H5N1 influenza virus, A H7N9 influenza virus, A H3N2 influenza virus.
  • the medicine for treating or preventing influenza virus infection includes a first active ingredient of the medicine and a second active ingredient of the medicine, and the first active ingredient of the medicine includes colimycin, isovalerylspiramycin I, and isoamyl One of acylspiramycin II, isovalerylspiramycin III, or a combination of two or three of isovalerylspiramycin I, isovalerylspiramycin II, and isovalerylspiramycin III;
  • the second active ingredient of the drug is selected from antiviral drugs and immunity enhancing drugs.
  • the first active ingredient of the medicine and the second active ingredient of the medicine can be a separate preparation, or can be compounded into one preparation.
  • the fourth object of the present invention is to provide the use of isovalerylspiramycin compounds, or pharmaceutically acceptable salts thereof, or combinations thereof in the preparation of medicines for the treatment of HIV infection.
  • Further schemes include one of colimycin, isovalerylspiramycin I, isovalerylspiramycin II, isovalerylspiramycin III, or isovalerylspiramycin I, isovalerylspiramycin I Application of a combination of two or three kinds of Iovalerylspiramycin III in preparing medicines for the treatment of HIV infection.
  • the AIDS virus includes AIDS virus HIV-1 type and AIDS virus HIV-2 type.
  • it includes HIV-1 IIIB .
  • the medicine for treating HIV infection includes a first active ingredient of the drug and a second active ingredient of the drug, and the first active ingredient of the drug includes colimycin, isovalerylspiramycin I, and isovaleryl helix One of Iovalerylspiramycin II, isovalerylspiramycin III, or a combination of two or three of isovalerylspiramycin I, isovalerylspiramycin II, and isovalerylspiramycin III;
  • the active ingredients of the two drugs are selected from antiviral drugs and immunity enhancing drugs.
  • the first active ingredient of the medicine and the second active ingredient of the medicine can be a separate preparation, or can be compounded into one preparation.
  • the present invention has the following beneficial effects compared with the prior art:
  • the present invention provides the application of isovalerylspiramycin compounds, or their pharmaceutically acceptable salts, or their compositions in the preparation of anti-intestinal virus, herpes virus, influenza virus, and HIV infection drugs.
  • isovalerylspiramycin compounds or their pharmaceutically acceptable salts, or their compositions in the preparation of anti-intestinal virus, herpes virus, influenza virus, and HIV infection drugs.
  • drugs There are new uses of drugs, and it also provides an effective method for the treatment of diseases caused by the above viral infections, which has economic and social benefits.
  • Test principle Vero (African green monkey kidney) cells are used as the virus host, and the degree of inhibition of the virus to the Vero cells caused by the sample is determined.
  • Virus strain Enterovirus 71 H07 strain (EV71), provided by ATCC.
  • sample processing the sample (cleritromycin) is prepared into mother liquor with DMSO before use, and then diluted with RPMI 1640 culture medium to a certain concentration and then diluted 3 times, a total of 8 dilutions.
  • Positive control drug Ribavirin (RBV), Hubei Tianyao Pharmaceutical Co., Ltd. (Lot No. 31712252), using RPMI 1640 culture medium as a solvent, filtered and sterilized for use.
  • Virus inhibition test method inoculate Vero cells in a 96-well culture plate, add 100ul of 4 ⁇ 10 5 /ml cell suspension to each well, 24 hours later, each well will be infected with enterovirus 71 type 10 -5 and adsorb 2 After hours, discard the virus solution, add maintenance solution containing samples of different dilutions and positive control drugs, and set up cell control wells and virus control wells, 5% CO 2 , 37°C incubator for culture. Observe the cytopathic degree (CPE) of each group when the virus control group (CPE) reaches 4+, and use the Reed-Muench method to calculate the half toxic concentration (TC 50 ) of the sample to the cells and the half inhibitory concentration (IC 50 ). The test results are shown in Table 1.
  • cleritromycin has a certain inhibitory activity against enterovirus 71 (EV71).
  • EV71 enterovirus 71
  • Vero African green monkey kidney cells are used as the virus host to determine the degree of inhibition of the herpes simplex virus type 1 caused by the Vero cell pathology.
  • Virus strain HSV-1F strain (VR733), provided by ATCC.
  • DMSO is made into mother liquor, and then diluted with RPMI 1640 culture medium to a certain concentration and then diluted 3 times, a total of 8 dilutions.
  • Positive control drug acyclovir (ACV), produced by Hubei Keyi Pharmaceutical Factory, using RPMI 1640 culture medium as solvent, filtered and sterilized, and ready for use.
  • ACV acyclovir
  • Virus inhibition test method Vero cell type 96-well culture plate, add 100ul of 4 ⁇ 10 5 /ml cell suspension to each well, add herpes virus type 1 10 -4 to each well after 24 hours, and adsorb for 2 hours. Discard the virus solution, add maintenance solution containing samples of different dilutions and positive control drugs, and set up cell control wells and virus control wells at the same time.
  • virus control group disease degree CPE
  • CPE cytopathic degree
  • Use Reed-Muench method to calculate the half inhibitory concentration (IC 50 ) of the samples against herpes simplex virus type 1 respectively.
  • MDCK dog kidney cells are used as the virus host to determine the degree of cytopathic effect (CPE) caused by the virus by the sample.
  • Virus strain influenza virus A/FM/1/47 (H1N1), cultured in the allantoic cavity of chicken embryos (2018.3), stored at -80°C.
  • Positive control drug Ribavirin (RBV), Hubei Tianyao Pharmaceutical Co., Ltd. (batch number 31712252). Oseltamivir phosphate was subpackaged by Shanghai Roche Pharmaceutical Co., Ltd. (batch number SH0071). Respectively use RPMI 1640 culture medium as the solvent, filter and sterilize, and set aside.
  • Virus inhibition test method MDCK cells were inoculated in a 96-well culture plate, and 100ul of 4 ⁇ 10 5 /ml cell suspension was added to each well, placed in 5% CO 2 and cultured at 37°C. After 24 hours, each well was infected with influenza virus 1/2 10 -5 , adsorbed for 2 hours, discarded the virus solution, added maintenance solution containing samples of different dilutions and positive control drugs, set up cell control wells and virus control wells at the same time, 5% CO 2. Cultivate at 37°C.
  • CPE cytopathic degree
  • the tested sample has certain inhibitory activity against influenza virus A/FM/1/47.
  • the result of the positive control drug is consistent with the previous results of our laboratory.
  • the test system is established. The results are credible.
  • MDCK dog kidney cells are used as the virus host to determine the degree of cytopathic effect (CPE) caused by the virus by the sample.
  • Virus strain Avian influenza virus A/Duck/Jiangsu/Sheyang/2004 (H5N1) virus strain was isolated, identified and preserved by the Key Open Laboratory of Livestock and Poultry Infectious Diseases, Ministry of Agriculture, Yangzhou University. The above-mentioned tests are all conducted in Yangzhou University Animal Biosafety The third-level laboratory is completed.
  • MDCK dog kidney cells are used as the virus host to determine the degree of cytopathic effect (CPE) caused by the virus by the sample.
  • Virus strain Avian influenza virus A/Duck/Jiangsu/Sheyang/2004 (H5N1) virus strain was isolated, identified and preserved by the Key Open Laboratory of Livestock and Poultry Infectious Diseases, Ministry of Agriculture, Yangzhou University. The above-mentioned tests are all conducted in Yangzhou University Animal Biosafety The third-level laboratory is completed.
  • Virus inhibition test method MDCK cells were inoculated in a 96-well culture plate, and 100ul of 4 ⁇ 10 5 /ml cell suspension was added to each well, placed in 5% CO 2 and cultured at 37°C. After 24 hours, each well was infected with 100TCID 50 influenza virus. After adsorption for 1 hour, the virus solution was discarded, and the maintenance solution containing different dilution samples and positive control drugs was added. At the same time, cell control wells and virus control wells were set up, 5% CO 2 , 37°C to cultivate. When the degree of disease in the virus control group (CPE) reaches 3+ or more, the hemagglutination test is used to detect the virus titer in each well.
  • CPE degree of disease in the virus control group
  • MDCK dog kidney cells are used as the virus host to determine the degree of cytopathic effect (CPE) caused by the virus by the sample.
  • Virus strain Influenza virus A/Hterrorism/359/95 (H3N2), cultured in the allantoic cavity of chicken embryos (2018.3), stored at -80°C.
  • sample processing The sample is prepared into mother liquor with DMSO before use, and then diluted with culture solution 3 times, each with 8 dilutions.
  • Positive control drug Ribavirin (RBV), Hubei Tianyao Pharmaceutical Co., Ltd. (batch number 31712252). Oseltamivir phosphate was subpackaged by Shanghai Roche Pharmaceutical Co., Ltd. (batch number SH0071). Respectively use RPMI 1640 culture medium as the solvent, filter and sterilize, and set aside.
  • Virus inhibition test method MDCK cells were inoculated in a 96-well culture plate, and 100ul of 4 ⁇ 10 5 /ml cell suspension was added to each well, placed in 5% CO 2 and cultured at 37°C. After 24 hours, each well was infected with influenza virus 1/3 10 -5 , adsorbed for 2 hours, discarded the virus solution, added maintenance solution containing samples of different dilutions and positive control drugs, set up cell control wells and virus control wells at the same time, 5% CO 2. Cultivate at 37°C.
  • CPE cytopathic degree
  • the cytotoxicity detection method includes: on a 96-well flat bottom plate, each sample was diluted with a 3-fold gradient with culture medium, and then 100ul of 4 ⁇ 10 was added to each well. 5 /ml of cell suspension, then adjust each well to a final volume of 200u1 with complete medium, and set a control well for normal cells at 37°C and 5% CO 2 incubator.
  • the samples to be tested are climycin, isovalerylspiramycin I, isovalerylspiramycin II, and isovalerylspiramycin III, all produced by Shenyang Tonglian Group Co., Ltd.
  • the samples to be tested are all dissolved in DMSO, the concentration of the sample stock solution is 50mM, and the storage condition is -20°C.
  • the positive control compound azidothymidine (AZT) was purchased from Sigama, using RPMI 1640 as the solvent, filtered and sterilized, and stored at -20°C after aliquoting.
  • RPMI 1640 medium (Invitrogen), containing 10% calf serum (Invitrogen), 2mM glutamine, 10mM HEPES, 50mM 2-mercaptoethanol, 100u/ml penicillin and streptomycin, filter sterilization,- Store at 20°C;
  • MTT Tetramethylazolium salt
  • SDS sodium dodecyl sulfonate
  • C8166 cells and H9 cells are T lymphocyte lines, which are donated by the British Medical Research Council (MRC), AIDS Reagent Project.
  • MRC British Medical Research Council
  • the cells were recovered, cultured, passaged and cryopreserved according to conventional methods, and cells in the logarithmic growth phase were used in each experiment.
  • the virus H9/HIV1 IIIB also gifted by MRC in the UK, is resuscitated, cultured, collected, subpackaged and frozen in accordance with conventional methods.
  • Biological safety cabinet carbon dioxide incubator, 96-well culture plate, inverted microscope, sterilization pot, high-speed refrigerated centrifuge.
  • H9 and C8166 cells were recovered, cultured, passaged and frozen in accordance with conventional methods. In each experiment, cells in the logarithmic growth phase were used.
  • H9/HIV-1 IIIB cells Resuscitate H9/HIV-1 IIIB cells, centrifuge at low speed, adjust the cell concentration to 4 ⁇ 10 5 /ml with RPM1-1640 complete medium, culture in a 37°C, 5% CO 2 incubator, supplement every three days The same amount of uninfected H9 cells in logarithmic growth phase. After a certain period of time, centrifuge at low speed, collect the culture supernatant, aliquot into cryopreservation tubes, and freeze at -70°C.
  • the HIV-1 IIIB supernatant was diluted 4-fold with complete medium to make 9 gradients, each with 6 wells, and a normal cell control at the same time.
  • the syncytium-inducible HIV strain (Syncytium Induced, SI) can induce the fusion of infected C8166 cells to form a giant cell fusion, that is, syncytia, whose volume is about 5 times larger than that of unfused cells. It can be clearly observed below.
  • the syncytium formation inhibition method based on this principle is a relatively sensitive detection method, and it is easy to determine whether the test sample has anti-HIV effect.
  • each sample was diluted 5-fold with culture medium. A total of 8 dilutions were set. Each gradient was set with 2 repeating wells. 4 ⁇ 10 4 C8166 cells were added to each well, and then each well Add 25 ⁇ l (1200TCID 50 ) of HIV-1 IIIB supernatant, the final volume of each well is 200 ⁇ l.
  • a negative control of normal cells, a positive control of virus without drug and a drug control of AZT were set up; they were cultured in a 37°C, 5% CO 2 incubator. 72 hours after infection, count the number of syncytia formed by HIV-1 IIIB- induced C8166 cells under an inverted microscope, and calculate the inhibition rate of syncytia formation with the following formula:
  • the EC 50 value (50% effective concentration) was further calculated by the Reed-Muench method, that is, the concentration at which the sample inhibits the formation of 50% syncytia.
  • the MTT colorimetric method is used to detect cytotoxicity, and the specific method is as follows:
  • each sample was diluted 5-fold with culture medium, and then 100ul of 4 ⁇ 10 5 /ml C8166 cell suspension was added to each well, that is, 4 ⁇ 10 4 cells were added to each well, and then Each well is adjusted to a final volume of 200u1 with complete medium, and a control well for normal cells is set at the same time, and cultured in a 37°C, 5% CO 2 incubator.
  • the Reed-Muench method was used to further calculate the CC 50 (50% cytotoxic concentration) value, which is the concentration at which the sample is toxic to 50% of the cells.
  • CC 50 is the sample concentration that inhibits 50% of the growth of C8166 cells
  • EC 50 is the sample concentration that inhibits 50% of C8166 cells from being infected by the virus and causes cytopathic changes
  • TI CC 50 /EC 50 .

Abstract

La présente invention concerne une application d'un composé d'isovalérylspiramycine et sa composition dans la préparation d'un médicament antiviral, en particulier une application de celui-ci dans la préparation d'un médicament contre l'entérovirus, le virus de l'herpès, le virus de la grippe ou l'infection par le virus du syndrome de l'immunodéficience acquise (SIDA), et comprenant en outre une application de l'une des substances suivantes : carrimycine, isovalérylspiramycine I, isovalérylspiramycine II ou isovalérylspiramycine III, ou une composition de deux ou trois des substances suivantes : isovalérylspiramycine I, isovalérylspiramycine II et isovalérylspiramycine III, dans la préparation d'un médicament contre l'entérovirus, le virus de l'herpès, le virus de la grippe ou l'infection par le virus du SIDA. La présente invention concerne une nouvelle utilisation d'un médicament existant, la fourniture d'un procédé efficace pour le traitement d'une maladie provoquée par l'entérovirus, le virus de l'herpès, le virus de la grippe ou l'infection par le virus du SIDA, et ayant des avantages économiques et des avantages sociaux.
PCT/CN2021/074401 2020-01-30 2021-01-29 Application du composé isovalérylspiramycine et sa composition pour la préparation d'un médicament antiviral WO2021151391A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010077555 2020-01-30
CN202010077555.1 2020-01-30

Publications (1)

Publication Number Publication Date
WO2021151391A1 true WO2021151391A1 (fr) 2021-08-05

Family

ID=77025289

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/074401 WO2021151391A1 (fr) 2020-01-30 2021-01-29 Application du composé isovalérylspiramycine et sa composition pour la préparation d'un médicament antiviral

Country Status (2)

Country Link
CN (1) CN113197912B (fr)
WO (1) WO2021151391A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105456283A (zh) * 2015-12-30 2016-04-06 中山大学 大环内酯类抗生素或其药用盐在制备抗手足口病药物中的应用
CN106726776A (zh) * 2016-12-30 2017-05-31 六安市裕安区天缘中药材种植专业合作社 多用途祛痘霜
CN107011333A (zh) * 2010-11-18 2017-08-04 耶鲁大学 具有募集抗体并对人体免疫缺陷病毒进入有抑制活性的双功能分子
CN109833326A (zh) * 2017-11-24 2019-06-04 苏州***医学研究所 大环内酯类抗生素在阻断流感病毒感染中的应用
CN111671762A (zh) * 2020-01-30 2020-09-18 沈阳福洋医药科技有限公司 酰基化螺旋霉素在制备治疗冠状病毒感染疾病药物上的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0727419T3 (da) * 1992-12-29 2002-06-10 Abbott Lab Mellemprodukter til fremstilling af forbindelser, som inhiberer retroviral protease

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107011333A (zh) * 2010-11-18 2017-08-04 耶鲁大学 具有募集抗体并对人体免疫缺陷病毒进入有抑制活性的双功能分子
CN105456283A (zh) * 2015-12-30 2016-04-06 中山大学 大环内酯类抗生素或其药用盐在制备抗手足口病药物中的应用
CN106726776A (zh) * 2016-12-30 2017-05-31 六安市裕安区天缘中药材种植专业合作社 多用途祛痘霜
CN109833326A (zh) * 2017-11-24 2019-06-04 苏州***医学研究所 大环内酯类抗生素在阻断流感病毒感染中的应用
CN111671762A (zh) * 2020-01-30 2020-09-18 沈阳福洋医药科技有限公司 酰基化螺旋霉素在制备治疗冠状病毒感染疾病药物上的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HOU LIPING: "Separation and Preparation Process of Isovaleryl Spiramycin Ⅲ", CHINESE MASTER’S THESES FULL-TEXT DATABASE, ENGINEERING SCIENCE AND TECHNOLOGY I, 15 June 2013 (2013-06-15), XP055832860 *

Also Published As

Publication number Publication date
CN113197912B (zh) 2023-02-03
CN113197912A (zh) 2021-08-03

Similar Documents

Publication Publication Date Title
CN108359644B (zh) 一种宽谱沙门氏菌噬菌体及其应用
Serkedjieva Antiviral activity of the red marine alga Ceramium rubrum
CN111233650B (zh) 一种抗病毒的蒽醌衍生物及其应用
CN111135184A (zh) GS-441524在制备新型冠状病毒SARS-CoV-2抑制剂中的应用
CN111096964A (zh) 一种槲皮素与抗菌药物的联合应用
Song et al. Antiviral effect of sulfated Chuanmingshen violaceum polysaccharide in chickens infected with virulent Newcastle disease virus
CN113491700B (zh) 牛磺罗定在抗病毒中的应用
CN106727623B (zh) 海藻低聚糖在制备抗禽白血病病毒制剂中的应用
CN112143709A (zh) 一株嗜水气单胞菌噬菌体及其应用
CN112353797B (zh) 吲哚-3-乙腈在制备治疗或预防流感病毒感染的药物中的应用
CN112641789A (zh) 一种化合物在治疗和预防新型冠状病毒和流感病毒药物方面的应用
KR20160019834A (ko) 음양곽 추출물을 유효성분으로 함유하는 항 바이러스용 조성물
CN113197912B (zh) 异戊酰螺旋霉素类化合物及其组合物在制备抗病毒药物中的应用
Saadh Potent antiviral effect of green synthesis silver nanoparticles on Newcastle disease virus
TWI763916B (zh) 藍綠藻萃取物及其製備方法與用途
Hizam et al. Antiviral efficacy of garlic oil against Newcastle disease virus
CN113521261A (zh) 一种抗冠状病毒和细菌双重纳米免洗消毒凝胶及其制备方法和应用
CN103800320B (zh) 含有炎琥宁及其药学上可接受的盐的药物组合物在制备兽用免疫增强剂方面的用途
CN106957826B (zh) 一种病毒灭活剂及其应用
EP3890754B1 (fr) Dérivé de polystyrène sulfoné destiné à être utilisé dans le traitement et/ou la prophylaxie de la pneumonite féline
CN112891343B (zh) 3-吲哚乙腈在制备抑制新型冠状病毒SARS-CoV-2药物中的应用
CN113440562B (zh) 复方鱼腥草合剂在制备预防或治疗冠状病毒药物中的应用
CN105943540A (zh) 一种西米杜鹃醇的用途
Abdelwahab et al. Potential antiviral activity of metformin against human Adenovirus-7
CN112957388B (zh) 甘蓝型油菜-菘蓝e单体附加系在抑制流感病毒中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21747913

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21747913

Country of ref document: EP

Kind code of ref document: A1