CN109864990B - Application of palicatin in preparation of anti-filovirus infection medicines - Google Patents
Application of palicatin in preparation of anti-filovirus infection medicines Download PDFInfo
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Abstract
The invention discloses an application of palicatin in resisting filovirus infection. The invention encompasses the use of palicati for the prevention or treatment of a filovirus infection or in combination with other antiviral drugs.
Description
Technical Field
The invention relates to application of Balicitib (CAS: 354813-19-7) in resisting filovirus infection, belonging to the technical field of medicines. The invention encompasses the use of palicati, alone or in combination, in the prevention or treatment of filoviruses.
Background
Filoviruses belong to the family Filoviridae (Filoviridae) and include three viruses: ebola virus (Ebolavirus, EBOV), marburg virus (Marburgvirus, MARV), kutava virus (cuevavus, LLOV). Ebola and Marburg are both controlled viruses, classified as class A bioterrorism agents, and live viruses need to be completed in biosafety level 4 (P-4) laboratory procedures [ Centers for Disease Control and Prevention/National Institutes of Health, biological in Microbiological and biological laboratories.4 th. Washington, DC: U.S. department of Health and Human Services, U.S. Top priority Office; 1999 DHHS Publication CDC 93-8395.]. After the human is infected with the two viruses, Ebola hemorrhagic fever and Marburg hemorrhagic fever can be caused, and the lethality rates can respectively reach 90% [ Feldmann H, Geisbert TW. Ebola haemomorrhagic feber. Lancet.2011; 377(9768):849-862.]And 80% [ Knipe DM, Howley PM. fields Virology, 6%th Edition[M].Philadelphia:Wolters Williams&Wilkins Health,2013:923-592]. The Quivala virus was found in 2002 in bats in a cave in Spain, and it has not been clarified yet whether the virus could cause human diseases [ Negredo A, Palacios G, V a zquez-Mor Lo n S, et ale Filovirus in Europe.PloS Pathogens,2011,7(10):e1002304]。
Filoviruses are single-stranded negative-strand RNA viruses with a genome length of about 19kb and a sequential order of genes 3'-NP-VP35-VP40-GP-VP30-VP24-L-5', encoding the virus surface glycoprotein GP and other 6 viral proteins [ Feldmann h. ebola-a Growing threadn Engl J Med 2014; 371:1375-1378]. EBOV is divided into 5 subtypes: zaire-type (Zaire-EBOV), Sudan-type (Sudan-EBOV), Leston-type (Reston-EBOV), CottdeWa-type (Zaire-EBOV) ((Zaire-EBOV))
Forest-EBOV) and Bendibuyo (Bundbugyo-EBOV), wherein the zaire type has the strongest lethality which can reach 90%. Until now, both MARV and LLOV have only one type of typing. FIG. 10 is a graph of the evolution of a filovirus gene according to the filovirus gene, using MEGA7 software, wherein the strains referred to in the examples of this patent are underlined.
The envelope Glycoprotein (GP) of filamentous viruses is the only viral protein that mediates entry of filamentous viruses into host cells. GP protein precursor is cleaved by Furin (Furin) to yield both GP1 and GP2 subunits. GP1 recognizes and binds to host cell surface specific receptors, the virus is then endocytosed into inclusion bodies and transported to lysosomes, under the acidic environment of lysosomes GP2 allosterises and mediates fusion of the Viral envelope and the lysosomal membrane, finally releasing the genetic material of the virus into the cytoplasm [ Takada a. filovirus Tropism: cellular molecules for Viral entry. frontiers in microbiology.2012; 3:34.]. The entry of the virus into the host cell is the first step of virus infection, and an entry inhibitor of the filovirus is searched and can effectively block the infection of the virus to the cell.
Ebola hemorrhagic fever and Marburg hemorrhagic fever are acute infectious diseases, with latency periods of 2-21 days, clinically characterized by fever, myalgia, headache, sore throat, vomiting, diarrhea, rash and impaired liver and kidney function, bleeding, and eventually hypotensive shock and even death [ strether LA Ebola virus Br J Biomed Sci 1999.56(4): 280-. In 2014, the epidemic situation of the most serious Ebola recorded in West Africa is outbreaked, and isolation, symptomatic treatment and supportive treatment, namely electrolyte and liquid balance maintenance, oxygen and blood pressure maintenance and treatment of secondary infection are mainly adopted [ Feldmann H, Geisbert TW. Ebola haemogranic feber. Lancet.2011.377(9768):849-862 ] are followed by attention and acceleration of the development process of drugs for resisting filarial viral hemorrhagic fever. The monoclonal antibody, ZMASP, was co-developed by the United states and Canada and entered phase II clinical trials in 2015. Assessment of plasma in convalescent phase is in clinical phase ii/iii, and small molecule Drugs such as RNA polymerase inhibitor plavir (T-705) are currently also progressing to clinical phase ii [ Bixler SL, Duplantier AJ, Bavari s.discovery Drugs for the Treatment of Ebola virus.current Treatment Options in infection diseases.2017; 9(3):299-317.]. The medicine only aims at the Ebola hemorrhagic fever, and the Marburg hemorrhagic fever has no therapeutic medicine at present.
Baricitat is a drug developed by Nowa for the treatment of osteoporosis in postmenopausal women. Its oral tolerance was good, but at phase ii clinical trial, the drug development was terminated when skin sclerosis occurred after subjects had been orally administered 50 mg/day for 9 months consecutively [ Chappard, libuban H, mindepth L, et al the Cathepsin K inhibitor AAE581 indexes pharmaceuticals in enzymic studies of clinical plaques. microscopic Research and technical. 2010; 73(7):726-732.]. Osteoporosis is caused by a decrease in bone metabolism, i.e., bone resorption is greater than bone formation, which leads to a decrease in total bone mass after menopause in women, and seriously affects quality of life [ Bossard MJ, Tomaszek TA, Levy MA, et al. mechanismins of Inhibition of catalysis K by force, Selective 1, 5-dicarboxylic azides: A New Class of Mechanism-Based Inhibition of thio proteins biochemistry,1999,38(48), pp 15893-15902 ]. Barrecanit is an inhibitor of cathepsin K, which inhibits excessive bone resorption by inhibiting osteoclastic type i collagen degradation. On the basis of literature search, no report about the activity of Balikat to filoviruses (including Ebola virus, Marburg virus, Quivala virus) or any antiviral activity is found.
The invention is based on the application of an Ebola virus infection model to evaluate various clinical in-research medicines, and the belicatin can block EBOV from infecting host cells. Studies have also shown that barrett also has inhibitory activity against marburg and kutah virus infected cells. Therefore, the palicati is considered to be a broad-spectrum inhibitor against the filovirus and has a clinical application prospect in treating hemorrhagic fever caused by the filovirus. The invention relates to a patent for new application of existing medicines.
Disclosure of Invention
The invention solves the technical problem of providing the application of the balacatin and the pharmaceutically acceptable salt thereof in preparing the medicaments for preventing or treating filovirus infection.
Specifically, in order to solve the technical problem of the invention, the following technical scheme is adopted:
the first aspect of the technical scheme of the invention provides an application of balacatin shown in a structural formula (I) and pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating filovirus
The pharmaceutically acceptable salt of the palicatide comprises pharmaceutically acceptable organic salt or inorganic salt, wherein the organic salt comprises sulfonate, carboxylate, amino acid salt and fatty acid salt, and the inorganic salt comprises hydrochloride, bromate, iodate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate and nitrate. Preferred are bisulfate, sulfate, hydrochloride and iodate.
The sulfonate comprises alkyl sulfonate containing 1-15 carbon atoms, benzene sulfonate, p-toluene sulfonate, o-toluene sulfonate and m-toluene sulfonate; carboxylates including tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; amino acid salts include glutamate and aspartate; the fatty acid salt comprises a long chain fatty acid salt having 2 to 18 carbon atoms.
The second aspect of the technical scheme of the invention provides application of a pharmaceutical composition in preparing an anti-filovirus drug, which is characterized in that the pharmaceutical composition comprises the palicatine shown in the structural formula (I) and pharmaceutically acceptable salts thereof as well as pharmaceutically acceptable carriers or excipients; the pharmaceutical composition may also contain other antiviral agents
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 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, solid or 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, 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 present invention, a wide variety of excipients well 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 can 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, etc.
The tablets may be further formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered 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 a 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 can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
The inventors of the present invention have found that palicatin specifically blocks infection of host cells by filoviruses. Can also be used in combination with other antiviral drugs.
For administration purposes, to enhance the therapeutic effect, the medicaments or pharmaceutical compositions of the invention may be administered by any known method of administration.
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.
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 has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
The filamentous virus according to the first and second aspects of the invention includes, but is not limited to, ebola virus, marburg virus, and kutavirus.
Such ebola viruses include, but are not limited to, zaire, sudan, leston, ketediw, and bendbury.
Advantageous technical effects
The results of phase II clinical tests of the barrecatin on postmenopausal women osteoporosis show that the barrecatin has good tolerance, the patients only have adverse reactions of skin sclerosis after taking 50 mg/day for 9 months continuously, and lesions disappear after taking the barrecatin and do not relapse within two years. Because the hemorrhagic fever course of the filovirus is short, and compared with the high pathogenicity and high lethality rate of the hemorrhagic fever of the filovirus, the side effect of the palicatin is very slight, the new application of the palicatin to the filovirus is considered to have high clinical value, and the new application of the palicatin to the filovirus is confirmed to be quickly applied to high-risk virus infection and alleviate epidemic situation.
Drawings
FIG. 1 Balikatin blocks the infectious activity of the Mayinga strain of Zaire-type Ebola virus.
FIG. 2. Balikat blocks the infectious activity of Makona strain of Zaire-type Ebola virus.
FIG. 3 Balikatin blocks Sudan-type Ebola virus infection activity.
FIG. 4 Balikatin blocks Cotediwa Ebola virus infection activity.
FIG. 5 Balikatin blocks the activity of Ebola Leston virus infection.
FIG. 6 Balikatin blocked the activity of Bndbur-type Ebola virus infection.
Figure 7 balicatt blocks marburg virus Musoke strain infectious activity.
Figure 8. barrett blocked marburg virus Ravn strain infectious activity.
FIG. 9 Balicat blocks the infectious activity of the Quiwa virus.
FIG. 10 is a filovirus gene clade (strains referred to in the examples of this patent are underlined).
Detailed Description
Examples Balika anti-filovirus Activity
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 capsuliform are key proteins for filovirus entry processes.
The invention uses filovirus envelope GP genes, which comprise Zaire type Ebola virus Mayinga strain envelope GP Gene (EBOV-Mayinga GP, Gene Access No. L11365), Zaire type Ebola virus Makona strain envelope GP Gene (EBOV-Makona GP, Gene Access No. KJ660346.2), Sudan type Ebola virus envelope GP Gene (EBOV-Sudan GP, Gene Access No. FJ968794.1), and Cotdie type Ebola virus envelope GP Gene (EBOV-
Forest GP, Gene Access No. FJ217162.1), Leston typeEbola virus envelope GP Gene (EBOV-Reston GP, Gene Access No. U23152.1), Bobby Pyrola virus envelope GP Gene (EBOV-Bundbugyo GP, Gene Access No. KR063673.1); marburg virus Musoke strain envelope GP Gene (MARV-Musoke GP, Gene Access No. DQ217792.1), Marburg virus Ravn strain envelope GP Gene (MARV-Ravn GP, Gene Access No. DQ447649.1); the quinava virus envelope GP Gene (LLOV GP, Gene Access No. JF828358.1). By co-transfection of GP protein plasmid and pNL4-3-Luc-R -E-Ebola recombinant virus EBOV-GP/HIV (Lennemann NJ, Rhein BA, Ndungo E, et al. comprehensive analysis of ebola virus GP1in viral entry. J Virol.2005) with filovirus GP as the shell to wrap HIV core is obtained; 79:4793-805.]Including Mayinga-GP/HIV, Makona-GP/HIV, Sudan-GP/HIV,
Forest-GP/HIV, Reston-GP/HIV, bundbugyo-GP/HIV; marburg recombinant virus MARV-GP/HIV [ Manicassamy B1, Wang J, Rumscchlag E, et al. Characterisation of Marburg virus glycoprotein in viral entry. virology.2007; 358:79-88]Including Musoke-GP/HIV, Ravn-GP/HIV; quintile recombinant virus LLOV-GP/HIV [ Maruyama J, Miyamoto H, Kajihara M, et al. 88(1) 99-109.doi 10.1128/JVI.02265-13.]. 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.
2. Experimental methods and results
The following strains were used in the present invention to evaluate the pharmacological activity of barlica against filovirus infection: ebola virus: EBOV-Mayinga (Gene Access No. L11365), EBOV-Makona (Gene Access;)on No.KJ660346.2)，EBOV-Sudan(Gene Accession No.FJ968794.1)，EBOV-
Forest (Gene Access No. FJ217162.1), EBOV-Reston (Gene Access No. U23152.1), EBOV-Bundbugyo (Gene Access No. KR063673.1); marburg virus: MARV-Musock (Gene Access No. DQ217792.1), MARV-Ravn (Gene Access No. DQ447649.1); the virus Quavav: LLOV (Gene Access No. JF828358.1).
Recombinant Virus preparation [ Chen Q, Tang K, Zhang XY, et al.Establishment of pseudoviral infection model for in vivo Pharmacodynamics evaluation of viral infection of beta Pharmaceutica Sinica B (2017), http:// dx. doi. org/10.1016/j. apsb.2017.08.003.]: co-transfection of 2. mu.g pcDNA3.1/EBOV-Mayinga GP plasmid and 2. mu.g pNL4-3-Luc-R-E-Plasmid to 293T cells, after transfection 48h, supernatant was collected and filtered through 0.45 μm filter, the filtrate contained Mayinga-GP/HIV virus particles, and the recombinant virus was used for infection. Ebola recombinant viruses were prepared according to the same method: Makona-GP/HIV, Sudan-GP/HIV, 
Forest-GP/HIV, Reston-GP/HIV, bundbugyo-GP/HIV; marburg recombinant virus: Musoke-GP/HIV, Ravn-GP/HIV; quinva recombinant virus: LLOV-GP/HIV virus particles.
Infection [ Chen Q, Tang K, Zhang XY, et al.expression of pseudoviral infection model for in vivo Pharmacodynamics evaluation of viral entry site B (2017), http:// dx. doi. org/10.1016/j. apsb.2017.08.003]: the day before infection, the ratio of each well is 6X 104Density of individual cells 293T cells were seeded onto 48-well plates. Test compounds were dissolved in DMSO. Test compounds were added to the cell culture medium 15 minutes prior to infection, blanketed with DMSO solvent, and then infected cells with virus fluid. After 48 hours of infection, the supernatant was discarded, 50. mu.l of cell lysate (Promega) was added to each well of infected cells to lyse the cells, and 30. mu.l of fluorescein was addedEnzyme substrates (Promega) were mixed with 20. mu.l of cell lysates and the Relative activities of cellular Luciferase (Relative Luciferase Units, RLUs) which reflect the level of viral infection were determined using an FB15 fluorescence detector (Sirius) instrument. The activity of the test compound against filoviruses is expressed as the inhibition rate (%) - (RLUs) Solvent control-RLUsDrug to be tested)/RLUsSolvent controlX 100. The results show that the palicatin can effectively inhibit the infection of host cells by the filoviruses, the results are shown in tables 1-3, and dose-response curves are shown in figures 1-9.
TABLE 1 Balika anti-Ebola recombinant virus (EBOV-GP/HIV) infection Activity
TABLE 2 Balikatin activity against Marburg recombinant virus (MARV-GP/HIV) infection
TABLE 3 Balikavi anti-Quikavi recombinant virus (LLOV-GP/HIV) infection Activity
Claims (6)
1. The use of balacatin and its pharmaceutically acceptable salts as shown in structural formula (I) in the preparation of medicaments for preventing or treating Ebola virus, Marburg virus or Quivala virus infection,
2. the use according to claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of pharmaceutically acceptable organic or inorganic salts, wherein said organic salt is selected from the group consisting of sulfonate, carboxylate, amino acid salt and fatty acid salt and said inorganic salt is selected from the group consisting of hydrochloride, bromate, iodate, sulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate and nitrate.
3. Use according to claim 2, characterized in that said sulfonate is selected from the group consisting of alkylsulfonates having 1 to 15 carbon atoms, benzenesulfonates, p-toluenesulfonates, o-toluenesulfonates, m-toluenesulfonates; the carboxylate is selected from tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; the amino acid salt is selected from glutamate and aspartate; the fatty acid salt is selected from long chain fatty acid salts containing 2-18 carbon atoms.
4. The application of a pharmaceutical composition in preparing a medicament for preventing or treating Ebola virus, Marburg virus and Quiver virus infection is characterized in that the pharmaceutical composition comprises Baricicatine shown in a structural formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients
5. The use according to claim 4, wherein said pharmaceutical composition further comprises an additional antiviral agent.
6. Use according to any one of claims 1 to 4, wherein the Ebola virus is selected from the group consisting of the Zaire type, the Sudan type, the Leston type, the Cotedawa type and the Bendbuck type.
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| 埃博拉病毒侵染细胞机制的研究进展;石明等;《病毒学报》;20130115;第29卷(第01期);71-75 * |
| 骨质疏松症药物治疗进展;戴哲浩等;《中国骨质疏松杂志》;20101120;第16卷(第11期);894-907 * |
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