Synthesis of DNA-Encoded Macrocyclic Peptides via Nitrile-Aminothiol Click Reaction
Lijun Fan, Yang Yu, Charles Jayne, John R. Frost, Jack D. Scott
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.
Topics & Concepts
ChemistryIntramolecular forceCombinatorial chemistryClick chemistryNitrilePeptideRing (chemistry)Substrate (aquarium)DNACondensation reactionAmino acidStereochemistryOrganic chemistryBiochemistryGeologyCatalysisOceanographyChemical Synthesis and AnalysisClick Chemistry and ApplicationsRNA and protein synthesis mechanisms