Sangamides are amide derivatives of sanglifehrin A, a cyclophilin-binding polyketide natural product which is structurally distinct from cyclosporine A. Cyclosporine A is the starting point for the synthesis of cyclophilin inhibitors such as alisporivir, currently in development for the treatment of HCV infection. We report here initial results of the optimisation program which led to identification of the sangamides, compounds that exhibit significantly improved potential for the treatment of chronic HCV infection.