Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection
Hansson, Magnus Joakim × Moss, Steven James Bobardt, Michael Chatterji, Udayan Coates, Nigel Garcia-Rivera, Jose A Elmér, Eskil Kendrew, Steve Leyssen, Pieter Neyts, Johan Nur-E-Alam, Mohammad Warneck, Tony Wilkinson, Barrie Gallay, Philippe Gregory, Matthew Alan #
Current Biology Ltd.
Chemistry & Biology vol:22 pages:285-292
Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.