De novo development of small cyclic peptides that are orally bioavailable

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The paper describes a method to develop small cyclic peptides that can bind to therapeutic targets with high affinity and specificity, and also be orally bioavailable. This could allow cyclic peptides to be developed as oral drugs. The method involves a two-step combinatorial synthesis approach to generate large libraries of cyclic peptides in a high-throughput manner. The peptides are cyclized via thioether bonds and then diversified by acylation of an amino group.

Using this method, the authors synthesized a library of 8,448 cyclic peptides and screened it against the therapeutic target thrombin. They identified several nanomolar binders. The cyclic peptides were then optimized for proteolytic stability, membrane permeability and metabolic stability through iterative cycles of synthesis and screening.

Ultimately, they developed a cyclic peptide thrombin inhibitor with 18% oral bioavailability in rats, approaching that of an optimized reference peptide. The approach provides a general methodology to develop cyclic peptide drugs that can be orally administered, which could expand therapeutic opportunities and address unmet medical needs. Key innovations are the thioether cyclization chemistry and two-step diversification strategy.

https://www.nature.com/articles/s41589-023-01496-y