Selcia publishes strategy for structural simplification of natural products

The paper outlines a technique to generate synthetically tractable cyclophilin inhibitors for the treatment of hepatitis C

Ciclosporin was originally taken from a fungus

Cyclophilin inhibitors are cyclosporin, a natural product first isolated from the fungus Tolypocladium inflatum in 1971, or cyclosporin derivatives. The generation of potent, drug-like molecules through chemical synthesis has been challenging.

In collaboration with Cypralis and Gilead Sciences, Selcia has delivered a set of synthetic macrocyclic cyclophilin inhibitors inspired by the core structure of the natural product sanglifehrin A.

The paper, published in the Journal of Medicinal Chemistry, 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 and modern synthetic methods.

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 has generated several patents jointly owned by Cypralis and Gilead.

Vicky Steadman, Director of Discovery at Selcia, said the project combined peptidyl prolyl isomerase biology with medicinal and synthetic chemistry and knowledge of structural biology.

Selcia specialises in the medicinal chemistry of macrocycles, including cyclic peptides, their simplification and optimisation for drug use together with a unique peptidyl prolyl isomerase (PPIase) inhibitor screening platform.

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