Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175.

Abstract

Shortened current direct-acting antiviral (DAA) therapies while less expensive, have not provided satisfactory efficacy in naïve cirrhotics, treatment experienced non-cirrhotics or even genotype-3 (GT3)-infected patients. Since DAA regimens consist of the same classes of inhibitors-NS5A (NS5Ai) and NS5B (NS5Bi) +/- NS3 (NS3i) inhibitors-it is likely that their costs will be high and will provide similar degrees of protection. Integrating drugs with distinct mechanisms of action (MoA) into DAA regimens could provide the solution for shortening the period of treatment. One such class of agents is the cyclophilin inhibitors (CypI), which has shown efficacy in patients. Resistance-associated variants persist for years post-treatment in patients exposed to NS5Ai or NS5Bi who fail to achieve a sustained virologic response, impairing their chance for cure on retreatment with existing DAA combinations. Because of their high barrier to resistance, CypI may be particularly useful as a rescue therapy for patients who have relapsed with DAA resistance-associated variants. In this study, we analyzed the anti-HCV properties of the novel cyclosporine A (CsA) derivate-STG-175. The non-immunosuppressive STG-175 possesses a high (EC50 11.5-38.9 nM) multi-genotypic (GT1a to 4a) anti-HCV activity. STG-175 clears cells from HCV since no viral replication rebound was observed after cessation of drug treatment. It presents a higher barrier to resistance than other CypI or selected DAAs. HCV variants, which emerged under STG-175 pressure, are only ~2-fold resistant to the drug. No cross-resistance was observed with DAAs STG-175 was efficacious against DAA-resistant HCV variants. Drug combination studies revealed that STG-175 provides additive and synergistic effects against GT1a to 4a. STG-175 inhibits the infection of HCV, HIV-1 and HBV in mono-, dual- and triple-infection settings. Altogether these results suggest that the new CypI STG-175 represents an attractive drug partner for IFN-free DAA regimens for the treatment of HCV and co-infections.