A Two-Step Synthesis of Covalent Genetically-Encoded Libraries of Peptide-Derived Macrocycles (cGELs) enables use of electrophiles with diverse reactivity.

ABSTRACT: Genetically-encoded libraries of peptide-derived macrocycles containing electrophile 'warheads' (cGELs) can be used to identify potent and selective covalent ligands for protein targets. Such cGELs are synthesized either by incorporation of unnatural amino acids that display mild electrophiles on their side chains or by chemical post-translational modification (cPTM) of mRNA or phage-displayed peptide libraries. Here we investigate fundamental barriers to the synthesis of cGELs. We observe that a previously reported cPTM that proceeds in neutral-to-basic conditions creates mixtures of regioisomers. The complexity of the resulting mixture scales with the electrophilicity of the warhead used in the linker, with some electrophiles being not suitable for use under basic conditions. In contrast

SUBMITTER: Walker JH 

PROVIDER: S-EPMC12407954 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature