CHAPTER 11: Optimization of Cyclophilin Inhibitors for Use in Antiviral Therapy

Cyclophilins are members of the Propyl Peptidase Isomerase (PPIase) family of proteins and have recently been found to be required for efficient replication and/or infectivity of several viruses. Cyclosporine A (CsA), the prototypical inhibitor of cyclophilins has shown good activity against several key viruses, including HIV‐1 and HCV, however the immunosuppressive activity of CsA precludes its use as an effective anti‐viral agent. Structural information derived from the ternary complex formed by CsA, cyclophilin A and calcineurin has allowed the design of non‐immunosuppressive derivatives of CsA that retain, and in some cases improve, antiviral activity toward hepatitis C. Chemical modification of CsA has led to compounds with improved pharmacokinetic properties and with reduced drug‐drug interaction potential. Non‐CsA derived inhibitors of cyclophilin A have recently been identified and hold promise as synthetically more tractable leads for cyclophilin‐based discovery projects.