Development of antiviral therapeutics combating coxsackievirus type B3 infection

Cover Page


Cite item

Full Text

Abstract

Enteroviruses comprise highly diverse group of single-stranded positive RNA viruses belonging to Enterovirus genus, Picornaviridae family. They are the most prevalent viruses worldwide highlighted by high resistance to environmental cues. Enteroviruses normally cause seasonal self-limiting infections, but also known as causative infectious agents of encephalitis, myocarditis, poliomyelitis, acute heart failure and sepsis. Enterovirus genetic plasticity contributes to widespread epidemics and sporadic outbreaks (e. g., outbreaks of Enterovirus D68 and Enterovirus 71). Type B Coxsackieviruses of Enterovirus B species is one of commonly identified infectious agents associated predominantly with mild upper respiratory and gastrointestinal illnesses. Nevertheless, Coxsackieviruses B3 infection can result in severe myocarditis leading ultimately to heart failure. The pathogenesis of Coxsackievirus B3-induced myocarditis is well known being mediated by both direct damage due to viral proteases and indirectly via secondary host immune responses. Despite success in preventive vaccination of some enterovirus infections that allowed to control some of them direct antiviral agents for treatment of enteroviral infection particularly Coxsackieviruses B3 myocardial infection are still in demand. In addition, no ongoing clinical trials for therapy or prevention of Coxsackieviruses B3 infection are available. Current treatment strategies are mainly aimed to stabilize patient condition and relieve discomfort condition. It seems that relatively small market for anti-enteroviral drugs prevents pharma industry from developing new drugs. The Coxsackieviruses B3 lifecycle have been extensively studied and potential targets for drug design have been identified. The aim of our review was to describe current state in the field of antiviral drug design combating Coxsackieviruses B3 infection emphasizing direct-acting antivirals, albeit paying some attention to host factor-targeting inhibitors (including compounds from medicinal plant extracts) as well. The following categories of direct Coxsackieviruses B3 inhibitors are discussed in detail: capsid binders (pleconaril and its derivatives), viral 3C protease inhibitors (rupintrivir and its analogs), drugs targeting viral replication (both nucleoside analogs and non-nucleoside inhibitors). Results of drug repurposing screens for amiloride, benzerazide, dibucaine and fluoxetine are also discussed.

About the authors

A. S. Volobueva

St. Petersburg Pasteur Institute

Author for correspondence.
Email: sasha-khrupina@mail.ru

Aleksandrina S. Volobueva - Researcher, Laboratory of Experimental Virology.

197101, St. Petersburg, Mira str., 14, Phone: +7 (921) 365-05-48 Russian Federation

V. V. Zarubaev

St. Petersburg Pasteur Institute

Email: zarubaev@gmail.com

PhD MD (Biology), Senior Researcher, Laboratory of Experimental Virology.

St. Petersburg

Russian Federation

K. S. Lantseva

St.Petersburg State University

Email: kashitsu@gmail.com

Student

St. Petersburg

Russian Federation

References

  1. Романенкова Н.И., Бичурина М.А., Розаева Н.Р., Канаева О.И., Шишко Л.А., Черкасская И.В., Кириллова Л.П. Вирусы Коксаки В1—6 как этиологический фактор энтеровирусной инфекции // Журнал инфектологии. 2016. Т. 8, № 2. С. 65—71.
  2. Abdelnabi R., Geraets J.A., Ma Y., Mirabelli C., Flatt J.W., Domanska A., Delang L., Jochmans D., Kumar T.A., Jayaprakash V., Sinha B.N., Leyssen P., Butcher S.J., Neyts J. A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses. PLoS Biol., 2019, vol. 17, no. 6: e3000281. doi: 10.1371/journal.pbio.3000281
  3. Ang M.J., Lau Q.Y., Ng F.M., Then S.W., Poulsen A., Cheong Y.K., Ngoh Z.X., Tan Y.W., Peng J., Keller T.H., Hill J., Chu J.J., Chia C.S. Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2-P4 study. J. Enzyme Inhib. Med. Chem., 2016, vol. 31, no. 2, pp. 332-339. doi: 10.3109/14756366.2015.1018245
  4. Bailey J.M., Tapprich W.E. Structure of the 5‘ nontranslated region of the coxsackievirus b3 genome: chemical modification and comparative sequence analysis. J. Virol., 2007, vol. 81, no. 2, pp. 650-668. doi: 10.1128/JVI.01327-06
  5. Blyszczuk P. Myocarditis in humans and in experimental animal models. Front. Cardiovasc. Med., 2019, vol. 6: 64. doi: 10.3389/fcvm.2019.00064
  6. Cai Z., Shen L., Ma H., Yang J., Yang D., Chen H., Wei J., Lu Q., Wang D.W., Xiang M., Wang J. Involvement of endoplasmic reticulum stress-mediated C/EBP homologous protein activation in Coxsackievirus B3-induced acute viral myocarditis. Circ. Heart Fail., 2015, vol. 8, no. 4, pp. 809-818. doi: 10.1161/circheartfailure.114.001244
  7. Chen J., Ye X., Zhang X.Y., Zhu Z., Zhang X., Xu Z., Ding Z., Zou G., Liu Q., Kong L., Jiang W., Zhu W., Cong Y., Huang Z. Coxsackievirus A10 atomic structure facilitating the discovery of a broad-spectrum inhibitor against human enteroviruses. Cell Discov., 2019, vol. 5, no. 4, 15 p. doi: 10.1038/s41421-018-0073-7
  8. Cornell C.T., Kiosses W.B., Harkins S., Whitton J.L. Coxsackievirus B3 proteins directionally complement each other to down-regulate surface major histocompatibility complex class I. J. Virol., 2007, vol. 81, no. 13, pp. 6785-6797. doi: 10.1128/JVI.00198-07
  9. Coyne C.B., Bergelson J.M. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell, 2006, vol. 124, no. 1, pp. 119-131. doi: 10.1016/j.cell.2005.10.035
  10. Dunn J.J., Bradrick S.S., Chapman N.M., Tracy S.M., Romero J.R. The stem loop II within the 5‘ nontranslated region of clinical coxsackievirus B3 genomes determines cardiovirulence phenotype in a murine model. J. Infect. Dis., 2003, vol. 187, no. 10, pp. 1552-1561. doi: 10.1086/374877
  11. Dutkiewicz M., Swiatkowska A., Ojdowska A., Smolska B., Dymarek-Babs T., Jasinska A., Ciesiolka J. Molecular mechanisms of genome expression of coxsackievirus B3 that belongs to enteroviruses. BioTechnologia, 2012, vol. 93, no. 4, pp. 414-423. doi: 10.5114/bta.2012.46595
  12. Graci J.D., Too K., Smidansky E.D., Edathil J.P., Barr E.W., Harki D.A., Galarraga J.E., Bollinger J.M. Jr., Peterson B.R., Loakes D., Brown D.M., Cameron C.E. Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues. Antimicrob. Agents Chemother., 2008, vol. 52, no. 3, pp. 971-979. doi: 10.1128/AAC.01056-07
  13. Groarke J.M., Pevear D.C. Attenuated virulence of pleconaril-resistant coxsackievirus B3 variants. J. Infect. Dis., 1999, vol. 179, no. 6, pp. 1538-1541. doi: 10.1086/314758
  14. Gruez A., Selisko B., Roberts M., Bricogne G., Bussetta C., Jabafi I., Coutard B., De Palma A.M., Neyts J., Canard B. The crystal structure of coxsackievirus B3 RNA-dependent RNA polymerase in complex with its protein primer VPg confirms the existence of a second VPg binding site on Picornaviridae polymerases. J. Virol., 2008, vol. 82, no. 19, pp. 9577-9590. doi: 10.1128/JVI.00631-08
  15. Harki D.A., Graci J.D., Galarraga J.E., Chain W.J., Cameron C.E., Peterson B.R. Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases. J. Med. Chem., 2006, vol. 49, no. 21, pp. 6166-6169. doi: 10.1021/jm060872x
  16. Hayden F.G., Herrington D.T., Coats T.L., Kim K., Cooper E.C., Villano S.A., Liu S., Hudson S., Pevear D.C., Collett M., McKinlay M. Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of 2 double-blind, randomized, placebo-controlled trials. Clin. Infect. Dis., 2003, vol. 36, no. 12, pp. 1523-1532. doi: 10.1086/375069
  17. Jagdeo J.M., Dufour A., Klein T., Solis N., Kleifeld O., Kizhakkedathu J., Luo H., Overall C.M., Jan E. N-terminomics TAILS identifies host cell substrates of poliovirus and Coxsackievirus B3 3C proteinases that modulate virus infection. J. Virol., 2018, vol. 92, no. 8: e02211-17. doi: 10.1128/JVI.02211-17
  18. Kim B.K., Cho J.H., Jeong P., Lee Y., Lim J.J., Park K.R., Eom S.H., Kim Y.C. Benserazide, the first allosteric inhibitor of Coxsackievirus B3 3C protease. FEBS Lett., 2015, vol. 589, no. 15, pp. 1795-1801. doi: 10.1016/j.febslet.2015.05.027
  19. Kim B.K., Ko H., Jeon E.S., Ju E.S., Jeong L.S., Kim Y.C. 2,3,4-Trihydroxybenzyl-hydrazide analogues as novel potent coxsackievirus B3 3C protease inhibitors. Eur. J. Med. Chem., 2016, vol. 120, pp. 202-216. doi: 10.1016/j.ejmech.2016.03.085
  20. Kishimoto C., Crumpacker C.S., Abelmann W.H. Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets. J. Am. Coll. Cardiol., 1988, vol. 12, no. 5, pp. 1334-1341. doi: 10.1016/0735-1097(88)92618-6
  21. Kwon B.E., Song J.H., Song H.H., Kang J.W., Hwang S.N., Rhee K.J., Shim A., Hong E.H., Kim Y.J., Jeon S.M., Chang S.Y., Kim D.E., Cho S., Ko H.J. Antiviral activity of oroxylin A against Coxsackievirus B3 alleviates virus-induced acute pancreatic damage in mice. PLoS One, 2016, vol. 11, no. 5: e0155784. doi: 10.1371/journal.pone.0155784
  22. Lee K., Kim D.E., Jang K.S., Kim S.J., Cho S., Kim C. Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion. Oncotarget, 2017, vol. 8, no. 70, pp. 115315—115325. doi: 10.18632/oncotarget.23258
  23. Lim B.K., Ju E.S., Lee Y.J., Jang S.A., Youn T.J., Jeon E.-S. RNA helicase (2C) inhibitor prevent enteroviral-mediated cardiomyopathy. Eur. Heart J., 2013, vol. 34, pp. 3502. doi: 10.1093/eurheartj/eht309.3502
  24. Lim B.K., Yun S.H., Ju E.S., Kim B.K., Lee Y.J., Yoo D.K., Kim Y.C., Jeon E.S. Soluble coxsackievirus B3 3C protease inhibitor prevents cardiomyopathy in an experimental chronic myocarditis murine model. Virus. Res., 2015, vol. 199, 8 p. doi: 10.1016/j.virusres.2014.11.030
  25. Liu Y., Wang C., Mueller S., Paul A.V., Wimmer E., Jiang P. Direct interaction between two viral proteins, the nonstructural protein 2C and the capsid protein VP3, is required for enterovirus morphogenesis. PLoS Pathog., 2010, vol. 6, no. 8: e1001066. doi: 10.1371/journal.ppat.1001066
  26. Ma Y., Abdelnabi R., Delang L., Froeyen M., Luyten W., Neyts J., Mirabelli C. New class of early-stage enterovirus inhibitors with a novel mechanism of action. Antiviral Res., 2017, vol. 147, pp. 67—74. doi: 10.1016/j.antiviral.2017.10.004
  27. Makarov V.A., Braun H., Richter M., Riabova O.B., Kirchmair J., Kazakova E.S., Seidel N., Wutzler P., Schmidtke M. Pyrazolopyrimidines: potent inhibitors targeting the capsid of Rhino- and Enteroviruses. Chem. Med. Chem., 2015, vol. 10, no. 10, pp. 1629-1634. doi: 10.1002/cmdc.201500304
  28. Muckelbauer J.K., Kremer M., Minor I., Diana G., Dutko F.J., Groarke J., Pevear D.C., Rossmann M.G. The structure of coxsackievirus B3 at 3.5 A resolution. Structure, 1995, vol. 3, no. 7, pp. 653-667. doi: 10.1016/S0969-2126(01)00201-5
  29. Ogram S.A., Boone C.D., McKenna R., Flanegan J.B. Amiloride inhibits the initiation of coxsackievirus and poliovirus RNA replication by inhibiting VPg uridylylation. Virology, 2014, vol. 464-465, pp. 87-97. doi: 10.1016/j.virol.2014.06.025
  30. Patick A.K., Binford S.L., Brothers M.A., Jackson R.L., Ford C.E., Diem M.D., Maldonado F., Dragovich P.S., Zhou R., Prins T.J., Fuhrman S.A., Meador J.W., Zalman L.S., Matthews D.A., Worland S.T. In vitro antiviral activity of AG7088, a potent inhibitor of human rhinovirus 3C protease. Antimicrob. Agents Chemother., 1999, vol. 43, no. 10, pp. 2444-2450. doi: 10.1128/AAC.43.10.2444
  31. Peischard S., Ho H.T., Theiss C., Strutz-Seebohm N., Seebohm G. A kidnapping story: how coxsackievirus B3 and its host cell interact. Cell Physiol. Biochem., 2019, vol. 53, no. 1, pp. 121-140. doi: 10.33594/000000125
  32. Pevear D.C., Tull T.M., Seipel M.E., Groarke J.M. Activity of pleconaril against enteroviruses. Antimicrob. Agents Chemother., 1999, vol. 43, no. 9, pp. 2109-2115. doi: 10.1128/AAC.43.9.2109
  33. Robinson S.M., Tsueng G., Sin J., Mangale V., Rahawi S., McIntyre L.L., Williams W., Kha N., Cruz C., Hancock B.M., Nguyen D.P., Sayen M.R., Hilton B.J., Doran K.S., Segall A.M., Wolkowicz R., Cornell C.T., Whitton J.L., Gottlieb R.A., Feuer R. Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog., 2014, vol. 10, no. 4: e1004045. doi: 10.1371/journal.ppat.1004045
  34. Schmidtke M., Wutzler P., Zieger R., Riabova O.B., Makarov V.A. New pleconaril and [(biphenyloxy)propyl]isoxazole derivatives with substitutions in the central ring exhibit antiviral activity against pleconaril-resistant coxsackievirus B3. Antiviral Res., 2009, vol. 81, no. 1, pp. 56-63. doi: 10.1016/j.antiviral.2008.09.002
  35. Shi. L., Xiong H., He J., Deng H., Li Q., Zhong Q., Hou W., Cheng L., Xiao H., Yang Z. Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackievirus and adenovirus in vitro and in vivo. Arch. Virol., 2007, vol. 152, no. 8, pp. 1447-1455. doi: 10.1007/s00705-007-0974-5
  36. Song J.H., Ahn J.H., Kim S.R., Cho S., Hong E.H., Kwon B.E., Kim D.E., Choi M., Choi H.J., Cha Y., Chang S.Y., Ko H.J. Manassantin B shows antiviral activity against coxsackievirus B3 infection by activation of the STING/TBK-1/IRF3 signalling pathway. Sci. Rep., 2019, vol. 9, no. 1: 9413. doi: 10.1038/s41598-019-45868-8
  37. Strating J.R., van der Linden L., Albulescu L., Bigay J., Arita M., Delang L., Leyssen P., van der Schaar H.M., Lanke K.H., Thibaut H.J., Ulferts R., Drin G., Schlinck N., Wubbolts R.W., Sever N., Head S.A., Liu J.O., Beachy P.A., De Matteis M.A., Shair M.D., Olkkonen V.M., Neyts J., van Kuppeveld F.J. Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein. Cell Rep., 2015, vol. 10, no. 4, pp. 600-615. doi: 10.1016/j.celrep.2014.12.054
  38. Thibaut H.J., van der Linden L., Jiang P., Thys B., Canela M.D., Aguado L., Rombaut B., Wimmer E., Paul A., Perez-Perez M.J., van Kuppeveld F., Neyts J. Binding of glutathione to enterovirus capsids is essential for virion morphogenesis. PLoS Pathog., 2014, vol. 10, no. 4: e1004039. doi: 10.1371/journal.ppat.1004039
  39. Ulferts R., de Boer S.M., van der Linden L., Bauer L., Lyoo H.R., Mate M.J., Lichiere J., Canard B., Lelieveld D., Omta W., Egan D., Coutard B., van Kuppeveld F.J. Screening of a library of FDA-approved drugs identifies several enterovirus replication inhibitors that target viral protein 2C. Antimicrob. Agents Chemother., 2016, vol. 60, no. 5, pp. 2627-2638. doi: 10.1128/AAC.02182-15
  40. Ulferts R., van der Linden L., Thibaut H.J., Lanke K.H., Leyssen P., Coutard B., De Palma A.M., Canard B., Neyts J., van Kuppeveld F.J. Selective serotonin reuptake inhibitor fluoxetine inhibits replication of Human enteroviruses B and D by targeting viral protein 2C. Antimicrob. Agents Chemother., 2013, vol. 57, no. 4, pp. 1952-1956. doi: 10.1128/AAC.02084-12
  41. Van der Linden L., Vives-Adrian L., Selisko B., Ferrer-Orta C., Liu X., Lanke K., Ulferts R., De Palma A.M., Tanchis F., Goris N., Lefebvre D., De Clercq K., Leyssen P., Lacroix C., Purstinger G., Coutard B., Canard B., Boehr D.D., Arnold J.J., Cameron C.E., Verdaguer N., Neyts J., van Kuppeveld F.J. The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family. PLoS Pathog., 2015, vol. 11, no. 3: e1004733. doi: 10.1371/journal.ppat.1004733
  42. Van der Schaar H.M., Leyssen P., Thibaut H.J., de Palma A., van der Linden L., Lanke K.H., Lacroix C., Verbeken E., Conrath K., Macleod A.M., Mitchell D.R., Palmer N.J., van de Poёl H., Andrews M., Neyts J., van Kuppeveld F.J. A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase Шв. Antimicrob. Agents Chemother., 2013, vol. 57, no. 10, pp. 4971-4981. doi: 10.1128/AAC.01175-13
  43. Xia H., Wang P., Wang G.C., Yang J., Sun X., Wu W., Qiu Y., Shu T., Zhao X., Yin L., Qin C.F., Hu Y., Zhou X. Human enterovirus nonstructural protein 2C ATPase functions as both an RNA helicase and ATP-independent RNA chaperone. PLoS Pathog., 2015, vol. 11, no. 7: e1005067. doi: 10.1371/journal.ppat.1005067
  44. Yun S.H., Lee W.G., Kim Y.C., Ju E.S., Lim B.K., Choi J.O., Kim D.K., Jeon E.S. Antiviral activity of coxsackievirus B3 3C protease inhibitor in experimental murine myocarditis. J. Infect. Dis., 2012, vol. 205, no. 3, pp. 491—497. doi: 10.1093/infdis/jir745
  45. Zautner A.E., Jahn B., Hammerschmidt E., Wutzler P., Schmidtke M. N- and 6-O-sulfated heparan sulfates mediate internalization of coxsackievirus B3 variant PD into CHO-K1 cells. J. Virol., 2006, vol. 80, no. 13,pp. 6629— 6636. doi: 10.1128/JVI.01988-05
  46. Zhang Y., Cao W., Xie Y.H., Yang Q., Li X.Q., Liu X.X., Wang S.W. The comparison of a-bromo-4-chlorocinnamaldehyde and cinnamaldehyde on coxsackie virus B3-induced myocarditis and their mechanisms. Int. Immunopharmacol., 2012, vol. 14, no. 1, pp. 107-113. doi: 10.1016/j.intimp.2012.06.007

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2021 Volobueva A.S., Zarubaev V.V., Lantseva K.S.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies