Synthetic PROTACs based on a depsipeptide macrocycle selectively degrade cyclophilin A and inhibit HIV-1

Abstract We have designed and characterised PROteolysis TArgeting Chimeras (PROTACs) active against the human protein cyclophilin A (CypA), a viral cofactor required for efficient replication of a series of unrelated viruses. Our cyclophilin PROTACs have fully synthetic macrocycle warheads derived from Sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporin A, and do not have immunosuppressive activity. They effectively degrade CypA, with selectivity over CypB, in a ubiquitin dependent manner and across a variety of cell lines and primary cells. Critically, CypA degradation underlies improved antiviral activity against HIV-1 in primary T cells compared to the non-PROTAC parental inhibitor. We propose that PROTACs targeting CypA to inhibit viral replication promise high antiviral potency, reduced evolution of viral resistance, and broad specificity for unrelated viruses.