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Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: e00126-18. doi: 10.1128/AAC.00126-18. Print 2018 Jul.

Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small-Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity.

Author information

1
Institut Mondor de Recherche Biomédicale, INSERM U955 Team 18, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
2
National Reference Center for Viral Hepatitis B, C, and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France.
3
Unité Génomique Virale et Vaccination, CNRS UMR 3569, Institut Pasteur, Paris, France.
4
Centre de Biochimie Structurale, INSERM, CNRS, Université de Montpellier, Montpellier, France.
5
Institut Mondor de Recherche Biomédicale, INSERM U955 Team 18, Hôpital Henri Mondor, Université Paris-Est, Créteil, France hakim.ahmed-belkacem@inserm.fr.
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Contributed equally

Abstract

Although members of the Flaviviridae display high incidence, morbidity, and mortality rates, the development of specific antiviral drugs for each virus is unlikely. Cyclophilins, a family of host peptidyl-prolyl cis-trans isomerases (PPIases), play a pivotal role in the life cycles of many viruses and therefore represent an attractive target for broad-spectrum antiviral development. We report here the pangenotypic anti-hepatitis C virus (HCV) activity of a small-molecule cyclophilin inhibitor (SMCypI). Mechanistic and modeling studies revealed that the SMCypI bound to cyclophilin A in competition with cyclosporine (CsA), inhibited its PPIase activity, and disrupted the CypA-nonstructural protein 5A (NS5A) interaction. Resistance selection showed that the lead SMCypI hardly selected amino acid substitutions conferring low-level or no resistance in vitro Interestingly, the SMCypI selected D320E and Y321H substitutions, located in domain II of the NS5A protein. These substitutions were previously associated with low-level resistance to cyclophilin inhibitors such as alisporivir. Finally, the SMCypI inhibited the replication of other members of the Flaviviridae family with higher 50% effective concentrations (EC50s) than for HCV. Thus, because of its chemical plasticity and simplicity of synthesis, our new family of SMCypIs represents a promising new class of drugs with the potential for broad-spectrum anti-Flaviviridae activity as well as an invaluable tool to explore the role of cyclophilins in viral life cycles.

KEYWORDS:

Flaviviridae; antiviral agents; broad-spectrum antiviral activity; cyclophilin inhibitors; hepatitis C virus; resistance; small molecule

PMID:
29760125
PMCID:
PMC6021681
DOI:
10.1128/AAC.00126-18
[Indexed for MEDLINE]
Free PMC Article

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