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Updated: Jul 12, 2025

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
Synthesis of DNA-Encoded Macrocyclic Peptides via Nitrile-Aminothiol Click Reaction
Lijun Fan1, Yang Yu1, Charles Jayne1
1Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Abstract:
DNA-encoded library (DEL) technology holds exciting potential for discovering novel therapeutic macrocyclic peptides (MPs). Herein, we describe the development of a DEL-compatible peptide macrocyclization method that proceeds via intramolecular click-condensation between 3-(2-cyano-4-pyridyl)-l-alanine (Cpa) and an N-terminal cysteine. Cyclization takes place spontaneously in a buffered aqueous solution and affords the cyclized products in excellent yields. The reaction exhibits a broad substrate scope and can be employed to generate MPs of variable ring size and amino acid composition.
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