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© Research
Publication : Antimicrobial agents and chemotherapy

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Antimicrobial agents and chemotherapy - 14 May 2018

Nevers Q, Ruiz I, Ahnou N, Donati F, Brillet R, Softic L, Chazal M, Jouvenet N, Fourati S, Baudesson C, Bruscella P, Gelin M, Guichou JF, Pawlotsky JM, Ahmed-Belkacem A

Link to Pubmed [PMID] – 29760125

Antimicrob. Agents Chemother. 2018 Jul;62(7)

Although members of the 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 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 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 family with higher 50% effective concentrations (ECs) 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- activity as well as an invaluable tool to explore the role of cyclophilins in viral life cycles.

https://www.ncbi.nlm.nih.gov/pubmed/29760125