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

Antimicrobial Agents and Chemotherapy
Quentin NeversAbdelhakim Ahmed-Belkacem

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. T...Continue Reading

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Citations

Dec 24, 2019·Expert Opinion on Investigational Drugs·Daren R UreRobert T Foster
Jan 26, 2021·Applied Microbiology and Biotechnology·Yating LiaoYanhua Zeng

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Methods Mentioned

BETA
FRET
fluorescence resonance
interaction assay
X-ray
transfection
PCR

Software Mentioned

- 2
TOME
SigmaPlot
SMILES
MarvinSketch
Frog2

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