Affinity selection-mass spectrometry with linearizable macrocyclic peptide libraries.

ABSTRACT: Despite their potential, the preparation of large synthetic macrocyclic libraries for ligand discovery and development has been limited. Here, we produce 100-million-membered macrocyclic libraries containing natural and nonnatural amino acids. Near-quantitative intramolecular disulfide formation is facilitated by rapid oxidation with iodine in solution. After use in affinity selection, treatment with dithiothreitol enables near-quantitative reduction, rendering linear peptide analogs for standard tandem mass spectrometry. We use these libraries to discover macrocyclic binders to cadherin-2 and anti-hemagglutinin antibody clone 12ca5. Structure-activity relationship studies of an initial cadherin-binding peptide [CBP; apparent dissociation constant (K_d) = 53 nanomol

SUBMITTER: Lee MA 

PROVIDER: S-EPMC11922053 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature