Selcia, with colleagues from Cypralis and Gilead Sciences Inc., have published in the Journal of Medicinal Chemistry a novel strategy of structural simplification of a natural product to generate synthetically tractable cyclophilin inhibitors for the treatment of HCV. 

Cyclophilin inhibitors on the market or in clinical trials are cyclosporin (a natural product) or cyclosporin derivatives; the generation of potent, drug-like molecules through chemical synthesis has been challenging. Selcia’s collaboration with Cypralis and Gilead delivered a set of synthetic macrocyclic cyclophilin inhibitors inspired by the core structure of the natural product sanglifehrin A.

The paper describes how novel macrocyclic non-immunosuppressive cyclophilin inhibitors, with high potency in both biochemical and antiviral assays were generated by employing structure based drug design, modern synthetic methods and deep understanding of the property profile required of a successful drug.

Vicky Steadman, Director of Discovery at Selcia, said: ‘This ambitious strategy was feasible due to the combination of expertise in peptidyl prolyl isomerase biology, medicinal and synthetic chemistry available at Selcia with the deep virology and structural biology knowledge and commitment to the project at Gilead.’

Mike Peel, CSO of Cypralis, said: ‘The discovery of completely synthetic and very potent cyclophilin inhibitors that fully reproduce the biology of a semi-synthetic natural product lead is a major breakthrough in this field. It opens up many new opportunities for Cypralis’ drug discovery programmes in conjunction with our colleagues at Selcia and Gilead.’

This approach of structural simplification of a natural product opens up multiple avenues for the generation of novel intellectual property, and has generated several patents that are jointly owned by Cypralis and Gilead.