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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Antiviral Agents / pharmacology*
  • Cyclophilin A / antagonists & inhibitors*
  • Cyclophilin A / metabolism
  • Cyclosporine / pharmacology
  • Drug Resistance, Viral / genetics
  • Hepacivirus / drug effects*
  • Hepacivirus / growth & development
  • Hepatitis C / drug therapy
  • Humans
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication / drug effects


  • Antiviral Agents
  • Viral Nonstructural Proteins
  • Cyclosporine
  • NS-5 protein, hepatitis C virus
  • Cyclophilin A
  • alisporivir