Cyclophilin inhibitors as antiviral agents

Cyclophilins (Cyps) are ubiquitous proteins that effect the cis–trans isomerization of Pro amide bonds, and are thus crucial to protein folding. CypA is the most prevalent of the ∼19 human Cyps, and plays a crucial role in viral infectivity, most notably for HIV-1 and HCV. Cyclophilins have been shown to play key roles in effective replication of a number of viruses from different families. A drug template for CypA inhibition is cyclosporine A (CsA), a cyclic undecapeptide that simultaneously binds to both CypA and the Ca(2+)-dependent phosphatase calcineurin (CN), and can attenuate immune responses. Synthetic modifications of the CsA scaffold allows for selective binding to CypA and CN separately, thus providing access to novel, non-immunosuppressive antiviral agents.