Synthesis of DNA-Encoded Macrocyclic Peptides via Nitrile-Aminothiol Click Reaction

• DOI: 10.1021/acs.orglett.3c03284
• Publication Date: 2023-10-27T17:28:29Z
• Authors: Lijun Fan; Yang Yu; Charles Jayne; John R. Frost; Jack D. Scott
• Keywords: Condensation reaction

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 buffered aqueous solution affords cyclized products excellent yields. The reaction exhibits broad substrate scope can be employed to generate MPs variable ring size amino acid composition.