Debio-025 inhibits HIV-1 by interfering with an early event in the replication cycle

Cyclophilin A is a peptidyl-propyl isomerase that binds the capsid (p24) protein of HIV-1 and facilitates replication. We report a cyclophilin inhibitor, a non-immunosuppressive cyclosporine analogue, Debio-025, that is about 15-times more potent than cyclosporine A and less toxic resulting in a selectivity index of more than 300. It was equally active against virus strains that were resistant toward inhibitors of the viral entry, fusion, or reverse transcription while it was not inhibitory to HIV-2 or SIVMAC. Mechanism of action studies demonstrate that Debio-025 inhibits the HIV-1 replication by interfering with an early stage of the viral replication cycle. Indeed, addition of Debio-025 could be postponed for 2 h before loosing its antiviral activity. The compound proved inactive against mutant viruses that are independent of cyclophilin A binding suggesting Debio-025 targets the cyclophilin A–capsid interaction.