CN105477007B - Application of macrolide medicine in resisting filovirus infection - Google Patents
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Abstract
The invention discloses application of macrolide medicines in resisting filovirus infection. The invention comprises the application of macrolide medicines in preventing or treating the infection of the filamentous virus, wherein the medicines with the structural characteristics of macrolides are selected from at least one of azithromycin, telithromycin, clarithromycin, carbomycin A, josamycin, griseofulvin, midecamycin, mickamycin, oleandomycin, spiramycin, oleandomycin, tulathromycin, fluoromycin, tilmicosin, romycin, quinthromycin, tacrolimus, pimecrolimus, sirolimus and amphotericin B.
Description
Technical Field
The invention relates to application of macrolide medicines in the aspect of resisting filovirus infection, and belongs to the technical field of medicines.
Background
Filoviridae (Filoviridae), also known as filoviruses, has only one genus, filoviruses (Filovirus). Filoviruses are enveloped viruses in a filamentous form, with a single-stranded negative-strand RNA genome, which includes two viruses, namely Ebola virus (EBOV) and Marburg virus (MBV), both of which are controlled viruses and require completion of biosafety level 4 (P-4) laboratory procedures [ Centers for Disasecontrol and preference/National Institutes of health.Biosafety in microbiology and biological laboratories.4th ed.Washington, DC: U.S. Desituated of Health and Human Services, U.S. Top Printing knowledge; DHHS Publication CDC 93-8395. Ebola Hemorrhagic Fever (EHF) is caused by Ebola virus, a serious virulent infectious disease that seriously jeopardizes public safety and human health, with a mortality rate as high as 50% -90% [ Sanchez, a.; geisbert, TW.; feldmann, h.filoviridae: Marburg and ebolaviruses.in: Knipe, DM.; howley, PM., editors, fields virology, Philadelphia, Lippincott Williams & Wilkins; 2006.1409-1448.]. Marburg virus also causes hemorrhagic fever with a mortality rate of 50-80% [ Nonfatal cases power underserved due to an undercoperational community; the filamentous virus is a single-stranded negative-strand RNA virus, enveloped by envelope glycoprotein GP, the only viral protein responsible for entry of the virus into the host, and has a helical nucleocapsid in the center, including genomic RNA and other 6 viral proteins [ Feldmann, H.; Geisbert, TW.; Jahrling, PB., et al. viral. in: Fauquet, C.; Mayo, MA.; Maniloff, J.; Desselger, U.S.; Ball., LA., edition. Virus. medium. J.: Vixomy: Viith report of the international electrotechnical tissues, 645.653-653 ], the filamentous virus gene tree [ Acrier, scientific. J.; the coding gene of the coding genes of the viral genes of the aforementioned genes, 2004.645-653 ], 3607. and the current coding gene of the viral genes of the aforementioned type IV, 3607, IV, S. environmental coding, IV, S. A. As shown in FIGS Sudan-type (Sudan-EBV), Leston-type (Reston-EBV), Cote's-lvoire-EBV and Bendbury-type (Bundbugyo-EBV), of which the Zaire-type is the most malignant and has a mortality rate of 90% or more.
Ebola hemorrhagic fever and marburg hemorrhagic fever are both common afflictions in humans and animals, are commonly susceptible to both humans and primates, and have reported cases of input mainly in african regions, the united states, uk, switzerland and the middle east. The clinical symptoms are sudden high fever, headache, myalgia, nausea, vomiting, diarrhea, etc., and the patient eventually dies from multiple organ bleeding failure, tissue necrosis [ street la. ebolavirus. br J Biomed sci.1999.56(4): 280-.
At present, no effective vaccine and therapeutic drug for filovirus exists, which mainly controls virus diffusion through precautionary measures, closely monitors epidemic situation and carries out isolation observation on suspicious patients with bleeding symptoms. The treatment method is mainly auxiliary and comprises the steps of balancing electrolyte and repairing platelets to prevent bleeding, and because serum of Ebola rehabilitators has no remarkable effect in treating diseases, common antiviral methods such as interferon and ribavirin are ineffective [ Heinz Feldmann, Thomas WGeisbert. Ebola haemorrhagic feber. Lancet.2011.377(9768):849-862 ], and no specific treatment method exists at present.
In the research and development of drugs for filoviruses [ Heinz Feldmann, Thomas W Geisbert Ebolahaemorrhagic mover Lantet 2011.377(9768):849-862 ]: (1) conventional antiviral therapies, such as ribavirin and interferon, are ineffective; (2) serotherapy, in which the serum of convalescent patients is used for passive immunotherapy of patients, the results are not conclusive; (3) antisense or interfering RNA therapy has been shown to be effective in murine and non-human primates. However, RNA interference therapy is limited by the premise of determining EBV subtype sequences and cannot cope with rapid diagnosis in the early stage of epidemic outbreak; (4) against the symptoms of EBV coagulopathy, the nematode-derived anticoagulant protein rNAPc2 was reported to be 33% effective in treating non-human primate infections.
The existing data indicate that the survival rate of patients is closely related to the virus amount, when the virus amount is less than 104.5patient survival rates for pfu/ml blood were greatly improved [ Geisbert TW, Hensley LE, Larsen T, et al. Patholonesis of Ebola haemomorrhagic feeder in cynomolgus macalls: evidence of reliable cell early and sustained targets of infection. am J Pathol. 2003; 163:2347-2370.]. Therefore, reducing the replication rate of the virus as much as possible and enabling the innate and acquired immune response of the host to overcome infection are important strategies for developing anti-filovirus drugs, and the development of inhibitors for blocking filovirus entry is of great significance.
Screening of antiviral drugs by using a host as a target is a hot spot in the field of current virology research. The entry of the virus requires the involvement of host proteins. Regarding the process of entry of filamentous viruses into hosts, cathepsin b and NPC1 proteins (Niemann Pick C1) in the intracellular inclusion bodies/lysosomes were found to be key factors in host response to filamentous virus invasion in 2005 and 2011, respectively. In addition, it was recently reported in 2014 that the phosphatidylserine receptor AXL on the surface of cell membrane is also an important EBV entry-related host factor [ Kartikcrandran et al, endogenous protein analysis, soft-eye blood Virus Glycoprotein IsNecessary for infection. science.2005.308:1643-1645 ].
Clinical macrolides are mostly antibiotics, and some of them are immunosuppressants. Macrolides, also known as macrocyclic lactones, are a group of drugs whose action is within a "macrocycle", i.e., a lactone ring that binds one or more deoxy sugars, most of which are erythromycinoses and deoxy sugar amines, within the structure. Macrocyclic structures contain different carbon parent nuclei and can be classified into 14-, 15-and 16-membered ring macrolides. 14-membered ring structures such as erythromycin, roxithromycin, clarithromycin; 15-membered ring structures such as azithromycin; 16-membered ring structures such as spiramycin, midecamycin, kitasamycin, josamycin, and the like.
Macrolides are classified into ketolides, acyllactones, carbamates and dehydrolactones according to their structural characteristics. Macrolide drugs are clinically most antibiotics, and macrolide antibiotics are selectively combined with 50S subunit of bacterial 70S ribosome to introduce the change of the structural phase, inhibit the activity and translocation of peptidyl transferase in the ribosome, prevent the synthesis of RNA-dependent protein of diseased bacteria and achieve the antibacterial effect. Endocrino antibiotics are bacteriostatic agents that only inhibit bacteria in the proliferative phase but are ineffective against bacteria in the resting phase [ Robert CG, et al. antibiotic AgentsChemothers 1990; 426 of May.
With the increasing understanding of macrolide compounds, pharmacological activities and clinical applications of macrolide compounds, in addition to antibacterial activity, have been studied and developed. Such as the development of macrolide immunosuppressants (such as tacrolimus, pimecrolimus, sirolimus); cardiovascular disease control [ Lip GYH, Beevers DG. Can we tangent area with anti-inflammatory Lancet.1997,350(9075):378 ]; the medicine is used for treating bullous emphysema [ the weight of the book, Maxinghe, clinical broadening application research of macrolide antibiotics, foreign medicine antibiotic brochure, 1999,20(6):253], and the like, but the antiviral effect of the medicine is not reported.
The invention discloses a method for commonly screening 1600 marketed drugs based on an Ebola virus infection model, and finds that drugs with macrolide structural characteristics can block EBOV from infecting host cells. We also evaluated macrolide drugs using the Marburg virus infection model and found that such drugs are also effective in inhibiting Marburg virus infection. We judge that drugs with structural features of macrolides block the infection process of filoviruses.
Disclosure of Invention
The invention solves the technical problem of providing the application of a class of medicines with macrolide structural characteristics in preparing medicines for preventing or treating filovirus.
The drugs with structural characteristics of macrolides include, but are not limited to, azithromycin, telithromycin, clarithromycin, carbomycin A, josamycin, griseofulvin, midecamycin, mickamycin, oleandomycin, spiramycin, oleandomycin, tulathromycin, fluoromycin, tilmicosin, romycin, quinthromycin, tacrolimus, pimecrolimus, sirolimus and amphotericin B. These may be used in combination of any one, two or more thereof.
The filovirus includes but is not limited to marburg virus.
The Ebola virus is of the Zaire type, Sudan type, Leston type, Cotedawa type, and Bendberg type. Preferably zaire type, sudan type,
The filovirus includes, but is not limited to, ebola virus.
Specifically, to solve the technical problem of the present invention, the following technical solutions are adopted:
the invention provides an application of azithromycin shown as a structural formula (I) in preparing a medicament for preventing or treating anti-filovirus.
In the application, the medicine is a medicine composition taking azithromycin shown in a structural formula (I) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of telithromycin shown in the structural formula (II) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition with telithromycin shown in structural formula (II) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of clarithromycin shown in the structural formula (III) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition containing clarithromycin represented by structural formula (III) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the carbomycin A shown as the structural formula (IV) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition comprising the carbomycin A shown in the structural formula (IV) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the josamycin shown in the structural formula (V) in preparing a medicament for preventing or treating filovirus.
In the above application, the drug is a pharmaceutical composition comprising josamycin represented by the structural formula (V) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the griseofulvin shown in the structural formula (VI) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition comprising the griseofulvin represented by the structural formula (VI) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of midecamycin shown in the structural formula (VII) in preparing a medicament for preventing or treating filovirus.
In the above application, the drug is a pharmaceutical composition containing midecamycin represented by the structural formula (VII) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the mickamycin shown in the structural formula (VIII) in preparing a medicament for preventing or treating anti-filovirus.
In the above application, the drug is a pharmaceutical composition comprising mickamycin represented by the structural formula (VIII) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the oleandomycin shown in the structural formula (IX) in preparing a medicament for preventing or treating filovirus.
In the application, the medicine is a medicine composition taking oleandomycin shown in a structural formula (IX) as an effective component.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of spiramycin shown in the structural formula (X) in preparing a medicament for preventing or treating filovirus.
In the above application, the drug is a pharmaceutical composition comprising spiramycin represented by structural formula (X) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the oleandomycin shown in the structural formula (XI) in preparing a medicament for preventing or treating filovirus.
In the application, the medicine is a medicinal composition taking acearundomycin shown in a structural formula (XI) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides the application of the tulathromycin shown in the structural formula (XII) in preparing a medicament for preventing or treating filovirus.
In the application, the medicine is a medicine composition taking tulathromycin shown in a structural formula (XII) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the fluoroerythromycin as shown in the structural formula (XIII) in preparing a medicine for preventing or treating filovirus.
In the above application, the medicament is a medicinal composition with the fluoroerythromycin represented by a structural formula (XIII) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of tilmicosin shown in the structural formula (XIV) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition containing tilmicosin represented by the structural formula (XIV) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the rokitamycin shown as the structural formula (XV) in preparing a medicament for preventing or treating anti-filovirus.
In the above application, the medicament is a pharmaceutical composition comprising rokitamycin represented by structural formula (XV) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of the quinorubicin shown as the structural formula (XVI) in preparing a medicament for preventing or treating anti-filovirus.
In the application, the medicine is a medicine composition taking the quinorubicin shown in the structural formula (XVI) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of tacrolimus shown in the structural formula (XVII) in preparing a medicament for preventing or treating anti-filovirus.
In the above application, the medicament is a pharmaceutical composition containing tacrolimus represented by the structural formula (XVII) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of pimecrolimus shown in the structural formula (XVIII) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition containing pimecrolimus represented by structural formula (XVIII) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of sirolimus shown in the structural formula (XIX) in preparing a medicament for preventing or treating filovirus.
In the above application, the medicament is a pharmaceutical composition containing sirolimus represented by the structural formula (XIX) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
The invention also provides application of amphotericin B shown as the structural formula (XX) in preparing a medicament for preventing or treating filovirus.
In the application, the medicine is a medicine composition taking amphotericin B shown in a structural formula (XX) as an active ingredient.
In the above application, the pharmaceutical composition further comprises other antiviral drugs.
In the above application, the filovirus includes Ebola virus and Marburg virus.
In a further aspect, the invention relates to pharmaceutical compositions comprising as active ingredient a compound of the invention. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or the mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and the mannitol, glucose and the like can be added as a propping agent when preparing freeze-dried powder injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
The inventor of the invention finds that the macrolide drugs azithromycin, telithromycin, clarithromycin, carbomycin A, josamycin, griseofulvin, midecamycin, mickamycin, oleandomycin, spiramycin, oleandomycin, tulathromycin, fluoroerythromycin, tilmicosin, romycin, quinthromycin, tacrolimus, pimecrolimus, sirolimus and amphotericin B can specifically block the infection of host cells by the filamentous viruses. Can also be used in combination with other antiviral drugs.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/kg body weight, preferably from 0.1 to 100mg/kg body weight, more preferably from 1 to 60mg/kg body weight, most preferably from 2 to 30mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
Advantageous technical effects
Azithromycin, telithromycin, clarithromycin, carbomycin A, josamycin, griseofulvin, midecamycin, mickamycin, oleandomycin, spiramycin, acerolomycin, tulathromycin, fluoromycin, tilmicosin, rotamycin, quinorubicin, and amphotericin B have been used clinically as antibacterial agents, tacrolimus, pimecrolimus, and sirolimus have also been used clinically as immunosuppressive agents, and the safety, drug metabolism characteristics, and toxic and side effects thereof have been clarified. The discovery of the new application of the two medicines to resisting the Ebola virus can quickly enable the two medicines to be applied to high-risk virus infection and relieve epidemic situations.
Drawings
Figure 1 azithromycin blocks ebola virus infectious activity.
FIG. 2. telithromycin blocks the activity of Ebola virus infection.
FIG. 3 Clarithromycin blocks the activity of Ebola virus infection.
FIG. 4. Spiromycin blocks the activity of Ebola virus infection.
FIG. 5 tilmicosin blocks Ebola virus infection activity.
FIG. 6 amphotericin B blocks the activity of Ebola virus infection.
Figure 7. tacrolimus blocks ebola virus infection activity.
Figure 8 azithromycin blocks marburg virus infectious activity.
Figure 9. telithromycin blocks marburg virus infection activity.
Figure 10 oleandomycin acetate blocks marburg virus infection activity.
Figure 11. spiramycin blocks marburg virus infection activity.
Figure 12 tacrolimus blocks marburg virus infection activity.
FIG. 13 is a tree of filovirus gene evolutions.
Detailed Description
Example 1 principle of screening model
Entry of filamentous viruses into host cells is the first step in viral infection, and inhibition of viral entry is effective in blocking viral infection. Glycoproteins (GPs) on the surface of filovirus envelopes are key proteins for the filovirus entry process.
We synthesized the envelope GP Gene (EBOV-Zaire GP, Gene Access No. L11365) of the Zaire Ebola virus and the Sudan Ebola diseaseVirus envelope GP Gene (EBOV-Sudan GP, Gene Access No. FJ968794.1) and Marburg virus envelope GP Gene (Marburg GP, Gene Access No. NC-001608.3). Expression of GP protein plasmid and pNL4-3-Luc-R by Co-transfection-E-EBOV recombinant virus EBV-GP/HIV with filovirus GP as the shell to wrap the core of HIV is available [ Manicassamy B, Wang J, Jiang H, Rong L. comprehensive analysis of ebola virus GP1 in viral entry. J Virol.2005; 79:4793-805.]And Marburg recombinant virus MGP/HIV [ Manica ssamy B, Wang J, et al. characterization of Marburg virus glycovirus in virology. virology.2007; 358:79-88]. The virus particle has the following characteristics: 1) the selectivity of the virus for the host cell depends on the nature of the GP; 2) because env, nef and vpr genes on the HIV vector are deleted, the virus can only enter host cells once and cannot replicate, so the virus is safe; 3) the HIV vector carries a luciferase reporter gene, so that infected cells express luciferase, and the degree of virus infection of the cells can be indicated by detecting the luciferase activity. Meanwhile, we also prepared VSV-G/HIV recombinant viruses with the glycoprotein of VSV (VSV-G) as the outer membrane protein as a model control group. Specific filovirus entry inhibitors are considered when the compound inhibits EBV-GP/HIV virus entry without significant inhibition of VSV-G/HIV virus entry.
Example 2 Experimental methods
In the invention, EBOV-Zaire (Gene Access No. L11365), EBOV-Sudan (Gene Access No. FJ968794.1) and Marburg (Gene Access No. NC-001608.3) are applied to evaluate the pharmacological activity of the macrolide against filovirus infection:
recombinant virus preparation [ Manicassamy B, Wang J, Jiang H, Rong L.comprehensive analysis of ebola virus GP1 in viral entry.J Virol.2005; 79:4793-805.]: co-transfection of 2. mu.g pcDNA3.1/EBOV-Zaire GP plasmid (or 2. mu.g pcDNA3.1/EBOV-Sudan GP plasmid or 2. mu.g pcDNA3.1/Marburg GP plasmid) and 2. mu.g pNL4-3-Luc-R-E-Plasmid is transferred to 293T cells, supernatant is collected 48 h after transfection, and is filtered by a 0.45 mu m filter membrane, and the supernatant contains EBOV-Zaire GP/HIV virus particles (or EBO)V-Sudan GP/HIV virions or Marburg GP/HIV virions), which can be used for infection. The VSV-G/HIV recombinant virus was prepared in the same manner.
Infection [ Manicassamy B, Wang J, Jiang H, Rong L.comprehensive analysis of ebola virus GP1 in viral entry.J Virol.2005; 79:4793-805.]: the day before infection, according to 6X 10 per well4Density of individual cells a549 cells were seeded onto 24-well plates. The positive control compound or the compound to be screened is dissolved in DMSO, added to the cell culture medium 15 minutes before infection, and the DMSO solvent is used as a blank control. The cells were infected by addition of appropriate dilutions of virus fluid. After 48 hours of infection, the supernatant was discarded, 50. mu.l of cell lysate (Promega) was added to each well of the infected cells to lyse the cells, 30. mu.l of luciferase substrate (Promega) was mixed with 20. mu.l of cell lysate and the relative activity of cellular luciferase was measured using an FB15 fluorescence detector (Sirius) instrument, the intensity of the activity reflecting the level of infection by the virus. The results show that macrolide drugs are effective in inhibiting infection of host cells by filoviruses, and the results are shown in tables 1, 2 and 3, and partial dose-response curves are shown in FIGS. 2-12.
TABLE 1 Effect of macrolide drugs on EBOV-Zaire recombinant Virus infection
TABLE 2 Effect of macrolide drugs on EBOV-Sudan recombinant Virus infection
TABLE 3 Effect of macrolide drugs on Marburg recombinant Virus infection
Example 3 cytotoxicity assays
The MTS method is used for measuring the cytotoxicity of all related medicaments on A549 and 293T cells, and the results show that azithromycin, telithromycin, clarithromycin, carbomycin A, josamycin, griseofulvin, midecamycin, mickamycin, oleandomycin, spiramycin, oleandomycin, tulathromycin, flurithromycin, tilmicosin, romycin, quinamycin, amphotericin B, tacrolimus, pimecrolimus and sirolimus have no cytotoxicity at the final concentration of 10 mu M.
Claims (5)
1. The application of the medicine with the structural characteristics of macrolides in preparing the medicine for preventing or treating filovirus is characterized in that the medicine with the structural characteristics of macrolides is at least one selected from clarithromycin, carbomycin A, josamycin, dirithromycin, midecamycin, mickamycin, oleandomycin, spiramycin, acearundomycin, tulathromycin, flurochromicin, tilmicosin, rotamycin, quinorubicin, tacrolimus, pimecrolimus, sirolimus and amphotericin B.
2. Use according to claim 1, wherein the filovirus is an ebola virus.
3. Use according to claim 2, characterized in that said ebola virus is of the zaire, sudan, leston, cotdetwa and bendibu type.
4. Use according to claim 1, wherein the filovirus is a marburg virus.
5. Use of azithromycin and telithromycin for the manufacture of a medicament for the prevention or treatment of an anti-marburg virus infection.
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