Expanding the Chemical Space of Mechanically Interlocked Peptides (MIPs) via Rational Design and Metabolite Profiling.

ABSTRACT: Mechanically interlocked peptides (MIPs) possess exceptional biological stability, making them promising scaffolds for therapeutic development. However, despite advances in biological and chemical synthesis, their accessible chemical space remains limited. In particular, practical methodologies and rational design principles for mechanically interlocking and stabilizing conventional linear peptides are still underdeveloped. Here, we present a robust strategy for peptide interlocking and stabilization using active-template Cu-(I)-catalyzed azide-alkyne cycloaddition (AT-CuAAC). Through systematic exploration of amino acid side chains, macrocycle size, peptide length, and reaction conditions, we established design guidelines and constructed a diverse library of interlocked short peptides. Th

SUBMITTER: Li A 

PROVIDER: S-EPMC12569674 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature