What Are the Pros and Cons of the Use of Host-targeted Agents Against Hepatitis C?

Overview

Journal Antiviral Res

Publisher Elsevier

Date 2014 Mar 4

PMID 24583032

Citations 15

Authors

Jean-Michel Pawlotsky

Affiliations

Soon will be listed here.

Abstract

Hepatitis C virus (HCV) therapy is living a revolution. Host-targeted agents (HTAs) block HCV production by interacting with host cell components. Because they target conserved host proteins, not variable viral proteins, HTAs have the potential for pangenotypic antiviral activity and a high barrier to resistance. Only two HTAs have reached clinical development, including specific inhibitors of cyclophilin A peptidyl-prolyl cis/trans isomerase activity and antagonists of microRNA-122. Cyclophilin inhibitors have proven to be relatively well tolerated and can be confidently used as backbones of all-oral, interferon-free regimens. In addition, HTAs such as cyclophilin inhibitors offer opportunities for "panviral" approaches when they target mechanisms common to viruses of the same or different families. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."

Citing Articles

Novel Pyrazino[1,2-]indole-1,3(2,4)-dione Derivatives Targeting the Replication of Viruses: Structural and Mechanistic Insights.

Giannakopoulou E, Akrani I, Mpekoulis G, Frakolaki E, Dimitriou M, Myrianthopoulos V Viruses. 2024; 16(8).

PMID: 39205212 PMC: 11360281. DOI: 10.3390/v16081238.

A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex.

Michon M, Muller-Schiffmann A, Lingappa A, Yu S, Du L, Deiter F Open Biol. 2024; 14(6):230363.

PMID: 38889796 PMC: 11285769. DOI: 10.1098/rsob.230363.

Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities.

Chowdhary S, Deka R, Panda K, Kumar R, Solomon A, Das J Mol Pharm. 2023; 20(8):3698-3740.

PMID: 37486263 PMC: 10410670. DOI: 10.1021/acs.molpharmaceut.2c01080.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Hajjo R, Sabbah D, Abusara O, Kharmah R, Bardaweel S Viruses. 2023; 15(2).

PMID: 36851782 PMC: 9966946. DOI: 10.3390/v15020568.

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex.

Michon M, Muller-Schiffmann A, Lingappa A, Yu S, Du L, Deiter F bioRxiv. 2021; .

PMID: 34931190 PMC: 8687465. DOI: 10.1101/2021.01.17.426875.

References

Feld J . The beginning of the end: what is the future of interferon therapy for chronic hepatitis C?. Antiviral Res. 2014; 105:32-8. DOI: 10.1016/j.antiviral.2014.02.005. View

Lohmann V . Hepatitis C virus RNA replication. Curr Top Microbiol Immunol. 2013; 369:167-98. PMC: 7122439. DOI: 10.1007/978-3-642-27340-7_7. View

Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V . Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013; 59(3):434-41. DOI: 10.1016/j.jhep.2013.04.035. View

Li Y, Gottwein J, Scheel T, Jensen T, Bukh J . MicroRNA-122 antagonism against hepatitis C virus genotypes 1-6 and reduced efficacy by host RNA insertion or mutations in the HCV 5' UTR. Proc Natl Acad Sci U S A. 2011; 108(12):4991-6. PMC: 3064388. DOI: 10.1073/pnas.1016606108. View

Frausto S, Lee E, Tang H . Cyclophilins as modulators of viral replication. Viruses. 2013; 5(7):1684-701. PMC: 3738956. DOI: 10.3390/v5071684. View

Paeshuyse J, Kaul A, De Clercq E, Rosenwirth B, Dumont J, Scalfaro P . The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology. 2006; 43(4):761-70. DOI: 10.1002/hep.21102. View

Puyang X, Poulin D, Mathy J, Anderson L, Ma S, Fang Z . Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors. Antimicrob Agents Chemother. 2010; 54(5):1981-7. PMC: 2863619. DOI: 10.1128/AAC.01236-09. View

Tsai W, Hsu S, Hsu C, Lai T, Chen S, Shen R . MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012; 122(8):2884-97. PMC: 3408747. DOI: 10.1172/JCI63455. View

Belaidi E, Decorps J, Augeul L, Durand A, Ovize M . Endoplasmic reticulum stress contributes to heart protection induced by cyclophilin D inhibition. Basic Res Cardiol. 2013; 108(4):363. DOI: 10.1007/s00395-013-0363-z. View

10.

Chevaliez S, Pawlotsky J . Interferons and their use in persistent viral infections. Handb Exp Pharmacol. 2008; (189):203-41. PMC: 7114994. DOI: 10.1007/978-3-540-79086-0_8. View

11.

Niepmann M . Hepatitis C virus RNA translation. Curr Top Microbiol Immunol. 2013; 369:143-66. DOI: 10.1007/978-3-642-27340-7_6. View

12.

Pawlotsky J . Treatment of chronic hepatitis C: current and future. Curr Top Microbiol Immunol. 2013; 369:321-42. DOI: 10.1007/978-3-642-27340-7_13. View

13.

Koh C, Liang T . What is the future of ribavirin therapy for hepatitis C?. Antiviral Res. 2014; 104:34-9. PMC: 6299454. DOI: 10.1016/j.antiviral.2014.01.005. View

14.

Tanaka Y, Sato Y, Sasaki T . Suppression of coronavirus replication by cyclophilin inhibitors. Viruses. 2013; 5(5):1250-60. PMC: 3712306. DOI: 10.3390/v5051250. View

15.

Zeisel M, Felmlee D, Baumert T . Hepatitis C virus entry. Curr Top Microbiol Immunol. 2013; 369:87-112. DOI: 10.1007/978-3-642-27340-7_4. View

16.

OLeary J, Chan J, McMahon C, Chung R . Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial. Hepatology. 2007; 45(4):895-8. DOI: 10.1002/hep.21554. View

17.

Coelmont L, Kaptein S, Paeshuyse J, Vliegen I, Dumont J, Vuagniaux G . Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors. Antimicrob Agents Chemother. 2008; 53(3):967-76. PMC: 2650540. DOI: 10.1128/AAC.00939-08. View

18.

Lanford R, Hildebrandt-Eriksen E, Petri A, Persson R, Lindow M, Munk M . Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science. 2009; 327(5962):198-201. PMC: 3436126. DOI: 10.1126/science.1178178. View

19.

Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A . The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology. 2008; 47(3):817-26. DOI: 10.1002/hep.22131. View

20.

Zhu Q, Li N, Han Q, Zhang P, Yang C, Zeng X . Statin therapy improves response to interferon alfa and ribavirin in chronic hepatitis C: a systematic review and meta-analysis. Antiviral Res. 2013; 98(3):373-9. DOI: 10.1016/j.antiviral.2013.04.009. View