Triazavirín by mohol byť novovu nádejou v súboji s koronavírusom 2 vyvolávajúcim ťažký akútny respiračný syndróm (SARS-CoV-2)

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Autori: Ivan Malík ^1,2; Jozef Čižmárik ²; Mária Pecháčová ²; Gustáv Kováč ¹; Lucia Hudecova ¹;
Pôsobisko autorov: Institute of Chemistry, Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Slovak Medical University in Bratislava, Slovak Republic ¹; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic ²
Vyšlo v časopise: Čes. slov. Farm., 2021; 70, 18-25
Kategória:
doi: https://doi.org/https://doi.org/10.5817/CSF2021-1-18

Súhrn

Od začiatku pandémie vysokoinfekčného ochorenia COVID-19 (Coronavirus Disease-19), ktoré je spôsobené koronavírusom 2 vyvolávajúcim ťažký akútny respiračný syndróm (Severe Acute Respiratory Syndrome Coronavirus 2; SARS-CoV-2), bol celosvetovo registrovaný veľký počet klinických štúdií, v ktorých sú hodnotené tisícky liečiv. Stratégia reprofilizácie liečiv, t.j. utilizácia liečiv, ktorých terapeutické použitie už bolo schválené v inej indikácii, získa čas a zníži náklady na liečbu dovtedy, kým budú lekárom a pacientom k dispozícii nové (relevantné) terapeutické alternatívy. Z tohto dôvodu je proti SARS-CoV-2 hodnotených aj mnoho zlúčenín, ktoré sú schválené alebo experimentálne používané v liečbe infekcií zapríčinených koronavírusom 1 vyvolávajúcim ťažký akútny respiračný syndróm (Severe Acute Respiratory Syndrome Coronavirus 1), koronavírusom vyvolávajúcim stredovýchodný respiračný syndróm (Middle East Respiratory Syndrome Coronavirus), vírusom ľudskej imunodeficiencie typu 1 (Human Immunodeficiency Virus type 1) alebo vírusmi chrípky (Influenza viruses). Triazavirín (TZV) je netoxickým širokospektrálnym antivirotikom, ktoré efektívne pôsobí proti rôznym kmeňom chrípky antigénneho typu A (Influenza Virus A, Orthomyxoviridae), t.j. prasacej chrípke (H1N1 alebo H3N2), vtáčej chrípke (H5N1, H5N2, H9N2 alebo proti vysokopatogénnemu kmeňu H7N3), kmeňom chrípky antigénneho typu B (Influenza Virus B, Orthomyxoviridae), respiračnému syncyciálnemu vírusu (Orthopneumovirus, Pneumoviridae), vírusu kliešťovej encefalitídy (Flavivirus, Flaviviridae), vírusu západonílskej horúčky (Flavivirus, Flavaviridae), vírusu horúčky Rift Valley (Phlebovirus, Buny-aviridae) a aj herpesvírusom (Simplexviruses, Herpesviridae). V kontexte terapie ochorenia COVID-19 táto zlúčenina pravdepodobne redukovala zápalové reakcie, a takto limitovala poškodenie vitálnych orgánov a oddialila eventualitu terapeutickej podpory. Výpočtové metódy in silico tiež indikovali relatívne uspokojivé väzbové afinity tohto ligandu k štruktúrnym (E)- a (S)-proteínom, neštruktúrnej proteáze podobnej 3-chymotrypsínu (3-CL^pro) SARS-CoV-2 a aj receptoru ľudí, enzýmu-2 konvertujúcemu angiotenzín-I (ACE-2). Interakcie medzi TZV a vírusovými štruktúrami alebo ACE-2-receptorom pre SARS-CoV-2 by mohli efektívne blokovať vstup patogéna do hostiteľskej bunky a tiež jeho intracelulárnu replikáciu. Sľubné terapeutické schémy pre liečbu COVID-19-pozitívnych pacientov by mohli spočívať vo vhodnej kombinácii inhibítora fúzie membrán (napr. umifenoviru) s inhibítorom syntézy a replikácie vírusovej RNA (TZV).

Klíčová slova:

SARS-CoV-2 – COVID-19 – reprofilizácia liečiv – triazavirín – štruktúrne proteíny – proteáza podobná 3-chymotrypsínu – ACE-2

Zdroje

1. Formi D., Cagliani R., Clerici R., Sironi M. Molecular evolution of human coronavirus genomes. Trends Microbiol. 2017; 25, 35–48, doi: 10.1016/j.tim.2016.09.001

2. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H., Wang W., Song H., Huang B., Zhu N., Bi Y., Ma X., Zhan F., Wang L., Hu T., Zhou H., Hu Zh., Zhou W., Zhao L., Chen J., Meng Y., Wang J., Lin Y., Yuan J., Xie Zh., Ma J., Liu W. J., Wang D., Xu W., Holmes E. C., Gao G. F., Wu G., Chen W., Shi W., Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395, 565–574, doi: 10.1016/S0140-6736(20)30251-8

3. Dömling A., Gao L. Chemistry and biology of SARS--CoV-2. Chem. 2020; 6, 1283–1295, doi: 10.1016/j.chempr.2020.04.023

4. Chung J. Y., Thorne M. N., Kwon Y. J. COVID-19 vaccines: The status and perspectives in delivery points of view. Adv. Drug Deliv. Rev. 2021; article in press (102 pp.), doi: 10.1016/j.arcmed.2020.12.009

5. Chen J., Wang R., Wang M., Wei G.-W. Mutations strengthened SARS-CoV-2 infectivity. J. Mol. Biol. 2020; 432, 5212–5226, doi: 10.1016/j.jmb.2020.07.009

6. Greaney A. J., Starr T. N., Gilchuk P., Zost S. J., Binshtein E., Loes A. N., Hilton S. K., Huddleston J., Eguia R., Crawford K. H. D., Dingens A. S., Nargi R. S., Sutton R. E., Suryadevara N., Rothlauf P. W., Liu Z., Whelan S. P. J., Carnahan R. H., Crowe Jr. J. E., Bloom J. D. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Cell Host Microbe 2021; article in press (24 pp.), doi: 10.1016/j.chom.2020.11.007

7. Li Q., Wu J., Nie J., Zhang L., Hao H., Liu Sh., Zhao Ch., Zhang Q., Liu H., Nie L., Qin H., Wang M., Lu Q., Li X., Sun Q., Liu J., Zhang L., Li X., Huang W., Wang Y. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell 2020; 182, 1284–1294, doi: 10.1016/j.cell.2020.07.012

8. Wang D., Li Z., Liu Y. An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics. J. Infect. Public Health 2020; 13, 1405–1414, doi: 10.1016/j.jiph.2020.07.004

9. Al Mamun Sohag A., Hannan M. A., Rahman S., Hossain M., Hasan M., Khan M. K., Khatun A., Dash R., Uddin M. J. Revisiting potential druggable targets against SARS‐CoV‐2 and repurposing therapeutics under preclinical study and clinical trials: A comprehensive review. Drug Dev. Res. 2021; article in press (24 pp.), doi: 10.1002/ddr.21709

10. Almasi F., Mohammadipanah F. Hypothetical targets and plausible drugs of coronavirus infection caused by SARS-CoV-2. Transbound. Emerg. Dis. 2021; article in press (15 pp.), doi: 10.1111/tbed.13734

11. Wu X., Yu K., Wang Y., Xu W., Ma H., Hou Y., Li Y., Cai B., Zhu L., Zhang M., Hu X., Gao J., Wang Y., Quin H., Wang W., Zhao M., Wu X., Zhang Y., Li L., Li K., Du Z., Mol B. W. J., Yang B. Efficacy and safety of triazavirin therapy for Coronavirus Disease 2019: A pilot randomized controlled trial. Engineering (Beijing) 2020; 6, 1185–1191, doi: 10.1016/j.eng.2020.08.011

12. Tsvetov V. M., Mirzaev K. B., Sychev D. A. Is it possible to use riamilovir to prevent infection and treat COVID-19? Klinicheskaya Praktika (In Russian) 2020; S4, 15–17, doi: 10.37489/2588-0519-2020-S4-15-17

13. Wu X., Yu K., Wang Y., Xu W., Ma H., Hou Y., Li Y., Cai B., Zhu L., Zhang M., Hu X., Gao J., Wang Y., Qin H., Zhao M., Zhang Y., Li K., Du Z., Yang B. The efficacy and safety of triazavirin for COVID-19: A trial protocol. Engineering (Beijing) 2020; 6, 1199–1204, doi: 10.1016/j.eng.2020.06.011

14. Ahamad S., Branch S., Harrelson S., Hussain M. K., Saquib M., Khan S. Primed for global coronavirus pandemic: Emerging research and clinical outcome. Eur. J. Med. Chem. 2021; 209, art. no. 112862 (23 pp.), doi: 10.1016/j.ejmech.2020.112862

15. Deyeva E. G., Rusinov V. L., Charushin V. N., Chupakhin O. N., Kiselev O. I. Antiviral preparation Triazavirin^®: From screening to clinical trials. Razrabotka i Registratsiya Lekarstvennykh Sredstv. (In Russian) 2014; 2, 144–151.

16. Tikhonova E. P., Kuzmina T. Yu., Andronova N. V., Tyushevskaya O. A., Elistratova T. A., Kuzmin A. E. Study of effectiveness of antiviral drugs (umifenovir, triazavirin) against acute respiratory viral infections. Kazan Med. J. 2018; 99, 215–223, doi: 10.17816/KMJ2018-215

17. Sologub T. V., Tokin I. I., Midikari A. S., Tsvetkov V. V. A comparative efficacy and safety of using antiviral drugs in therapy of patients with influenza. Infekssionnye Bolezni (In Russian) 2017; 15, 40–47, doi: 10.20953/1729-9225-2017-3-40-47

18. Verevshchikov V. K., Shemyakina E. K., Sabitov A. U., Batskalevich N. A. Modern etiotropic therapy of influenza and ARVI in adult patients with premorbid pathology. Antibiot. Khimioter. (Antibiotiki i khimioterapiia; In Russian) 2018; 63, 47–50.

19. Loginova S. Ya., Borisevich S. V., Rusinov V. L., Ulomskiy U. N., Charushin V. N., Chupakhin O. N. Toxicity of triazavirin, a novel Russian antiinfluenza chemotherapeutic. Antibiot. Khimioter. (Antibiotiki i khimioterapiia; In Russian) 2012; 57, 8–10.

20. Reshetnikova T. I. Study of the chronic toxicity of antiviral drug triazavirin. Zhurnal Veterinariya (In Russian) 2019; 8, 49–51, doi: 10.30896/0042-4846.2019.22.1.49-52

21. Cherkashchenko O. S. Influence of triazavirin on enzymes of detoxication activity. Medline.ru – Rossiyskiy Biomeditsinskiy Zhurnal (In Russian) 2011; 12, 458–463.

22. Kasianenko K. V., Lvov N. I., Maltsev O. V., Zhdanov K. V. Nucleoside analogues for the treatment of influenza: history and experience. Zhurnal infektologii (In Russian) 2019; 11, 20–26, doi: 10.22625/2072-6732-2019-11-3-20-26

23. Chupakhin O. N., Charushin V. N., Rusinov V. L. Scientific foundations for the creation of antiviral and antibacterial preparations. Her. Russ. Acad. Sci. 2016; 86, 206–212, doi: 10.1134/S1019331616030163

24. Kiselev O. I., Deeva E. G., Melnikova T. I., Kozeletskaia K. N., Kiselev A. S., Rusinov V. L., Charushin V. N., Chupakhin O. N. A new antiviral drug triazavirin: Results of phase II clinical trial. Vopr. Virusol. (Voprosy virulogii; In Russian) 2012; 57, 9–12.

25. Loginova S. Ya., Borisevich S. V., Maksimov V. A., Bondarev V. P., Kotovskaia S. K., Rusinov V. L., Charushin V. N., Chupakhin O. N. Therapeutic efficacy of triazavirin, a novel Russian chemotherapeutic, against Influenza Virus A (H5N1). Antibiot. Khimioter. (Antibiotiki i khimioterapiia; In Russian) 2011; 56, 10–12.

26. Loginova S. Ya., Borisevich S. V., Rusinov V. L., Ulomskiy U. N., Charushin V. N., Chupakhin O. N. Investigation of triazavirin antiviral activity against tick-borne encephalitis pathogen in cell culture. Antibiot. Khimioter. (Antibiotiki i khimioterapiia; In Russian) 2014; 59, 3–5.

27. Loginova S. Ya., Borisevich S. V., Rusinov V. L., Ulomskiy U. N., Charushin V. N., Chupakhin O. N., Sorokin P. V. Investigation of prophylactic efficacy of triazavirin against experimental forest-spring encephalitis on albino mice. Antibiot. Khimioter. (Antibiotiki i khimioterapiia; In Russian) 2015; 60, 8–11.

28. Vanevskaia E. A., Mandra J. V., Khonina T. G. The clinical study of efficiency of modern antiviral drugs for the topical treatment of Herpes simplex patients. Problemy stomatologii (In Russian) 2015; 11, 4–7, doi: 10.18481/2077-7566-2015-11-4-7

29. Voinkov E. K., Drokin R. A., Ulomskiy E. N., Slepukhin P. A., Rusinov V. L., Chupakhin O. N. Crystal structure of medicinal product triazavirin. J. Chem. Crystallogr. 2019; 49, 213–218, doi: 10.1007/s10870-018-0750-2

30. Li J., Zheng S., Chen B., Butte A. J., Swamidass J. S., Lu Z. A survey of current trends in computational drug repositioning. Brief. Bioinform. 2016; 17, 2–12, doi: 10.1093/bib/bbv020

31. Xue H., Li J., Xie H., Wang Y. Review of drug repositioning approaches and resources. Int. J. Biol. Sci. 2018; 14, 1232–1244, doi: 10.7150/ijbs.24612

32. Yang Z.-W., Zhao Y.-Z., Zang Y.-J., Wang H., Zhu X., Meng J.-J., Yuan X.-H., Zhang L., Zhang Sh.-L. Rapid structure-based screening informs potential agents for coronavirus disease (COVID-19) outbreak. Chin. Phys. Lett. 2020; 37, art. no. 058701 (10 pp.), doi: 10.1088/0256-307X/37/5/058701

33. Wu Q., Zhang Y., Lü H., Wang J., He X., Liu Y., Ye Ch., Lin W., Hu J., Ji J., Xu J., Ye J., Hu Y., Chen W., Li S., Wang Ju., Wang Ji., Bi Sh., Yang H. The E protein is a multifunctional membrane protein of SARS-CoV. Genomics Proteomics Bioinformatics 2003; 1, 131–144, doi: 10.1016/s1672-0229(03)01017-9

34. Mukherjee S., Bhattacharyya D., Bhunia A. Host-membrane interacting interface of the SARS coronavirus envelope protein: Immense functional potential of C-terminal domain. Biophys. Chem. 2020; 266, art. no. 106452 (13 pp.), doi: 10.1016/j.bpc.2020.106452

35. Acharya K. R., Sturrock E. D., Riordan J. F., Ehlers M. R. W. ACE revisited: a new target for structure-based drug design. Nat. Rev. Drug Discov. 2003; 2, 891–902, doi: 10.1038/nrd1227

36. Monteil V., Kwon H., Prado P., Hagelkrüys A., Wimmer R. A., Stahl M., Leopoldi A., Garreta E., Hurtado Del Pozo C., Prosper F., Romero J. P., Wirnsberger G., Zhang H., Slutsky A. S., Conder R., Montserrat N., Mirazimi A., Penninger J. M. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020; 181, 905–913, doi: 10.1016/j.cell.2020.04.004

37. Rusinov V. L., Sapozhnikova I. M., Ulomskii E. N., Medvedeva N. R., Egorov V. V., Kiselev O. I., Deeva E. G., Vasin A. V., Chupakhin, O. N. Nucleophilic substitution of nitro group in nitrotriazolotriazines as a model of potential interaction with cysteine-containing proteins. Chem. Heterocycl. Comp. 2015; 51, 275–280, doi: 10.1007/s10593-015-1695-4

38. Chupakhin O. N., Rusinov V. L., Ulomsky E. N., Medvedeva N. R., Sapozhnikova I. M. Alkylation of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]1,2,4-triazine(4Н)-7-one and interaction of the products with N-nucleophiles. Butlerov. Commun. 2012; 31, 43–50.

39. Karpenko I., Deev S., Kiselev O., Charushin V., Rusinov V., Ulomsky E., Deeva E., Yanvarev D., Ivanov A., Smirnova O., Kochetkov S., Chupakhin O., Kukhanova M. Antiviral properties, metabolism, and pharmacokinetics of a novel azolo-1,2,4-triazine-derived inhibitor of Influenza A and B Virus replication. Antimicrob. Agents Chemother. 2010; 54, 2017–2022, doi: 10.1128/AAC.01186-09

40. Morse J. S., Lalonde T., Xu S., Liu W. R. Learning from the past: Possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019‐nCoV. ChemBioChem 2020; 21, 730–738, doi: 10.1002/cbic.202000047

41. Pillaiyar T., Wendt L. L., Manickam M., Easwaran M. The recent outbreaks of human coronaviruses: A medicinal chemistry perspective. Med. Res. Rev. 2021; 41, 72–135, doi: 10.1002/med.21724

42. Warren T. K., Wells J., Panchal R. G., Stuthman K. S., Garza N. L., Van Tongeren S. A., Dong L., Retterer C. J., Eaton B. P., Pegoraro G., Honnold S., Bantia S., Kotian P., Chen X., Taubenheim B. R., Welch L. S., Minning D. M., Babu Y. S., Sheridan W. P., Bavari S. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 2014; 508, 402–405, doi: 10.1038/nature13027

43. Tchesnokov E. P., Feng J. Y., Porter D. P., Götte M. Mechanism of inhibition of Ebola Virus RNA-dependent RNA polymerase by remdesivir. Viruses 2019; 11, art. no. 326 (16 pp.), doi: 10.3390/v11040326

44. Brown A. J., Won J. J., Graham R. L., Dinnon K. H., Sims A. C., Feng J. Y., Cihlar T., Denison M. R., Baric R. S., Sheahan T. P. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019; 169, art. no. 104541 (10 pp.), doi: 10.1016/j.antiviral.2019.104541

45. Vankadari N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int. J. Antimicrob. Agents 2020; 56, art. no. 105998 (3 pp.), doi: 10.1016/j.ijantimicag.2020.105998

46. Gaisenok O. V. The use of viral RNA polymerase inhibitors in combination with a fusion inhibitor in the treatment of patients with COVID-19: hypothesis. Vopr. Virusol. (Voprosy virulogii; In Russian) 2020; 65, 167–175, doi: 10.36233/0507-4088-2020-65-3-167-175

47. Boriskin Y. S., Leneva I. A., Pécheur E.-I., Polyak S. J. Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr. Med. Chem. 2008; 15, 997–1005, doi: 10.2174/092986708784049658

48. Blaising J., Polyak S. J., Pécheur E.-I. Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014; 107, 84–94, doi: 10.1016/j.antiviral.2014.04.006

49. Ou X., Liu Y., Lei X., Li P., Mi D., Ren L., Guo L., Guo R., Chen T., Hu J., Xiang Z., Mu Z., Chen X., Chen J., Hu K., Jin Q., Wang J., Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 2020; 11, art. no. 1620 (12 pp.), doi: 10.1038/s41467-020-15562-9

50. Huang D., Yu H., Wang T., Yang H., Yao R., Liang Z. Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis. J. Med. Virol. 2021; 93, 481–490, doi: 10.1002/jmv.26256