Cysteine‐Specific Multifaceted Bioconjugation of Peptides and Proteins Using 5‐Substituted 1,2,3‐Triazines

Abstract

Peptide and protein postmodification have gained significant attention due to their extensive impact on biomolecule engineering and drug discovery, of which cysteine‐specific modification strategies are prominent due to their inherent nucleophilicity and low abundance. Herein, the study introduces a novel approach utilizing multifunctional 5‐substituted 1,2,3‐triazine derivatives to achieve multifaceted bioconjugation targeting cysteine‐containing peptides and proteins. On the one hand, this represents an inaugural instance of employing 1,2,3‐triazine in biomolecular‐specific modification within a physiological solution. On the other hand, as a powerful combination of precision modification and biorthogonality, this strategy allows for the one‐pot dual‐orthogonal functionalization of biomolecules utilizing the aldehyde group generated simultaneously. 1,2,3‐Triazine derivatives with diverse functional groups allow conjugation to peptides or proteins, while bi‐triazines enable peptide cyclization and dimerization. The examination of the stability of bi‐triazines revealed their potential for reversible peptide modification. This work establishes a comprehensive platform for identifying cysteine‐selective modifications, providing new avenues for peptide‐based drug development, protein bioconjugation, and chemical biology research.

Late-stage peptide modification and macrocyclization enabled by tertiary amine catalyzed tryptophan allylation

“…In line with our ongoing interest in peptide chemistry, including those Trp modifications, 33,39,42,45–49 we have been trying to explore more mild, easy-to-manipulate alternatives for peptide modification/functionalization to enrich the scenario. Promoted by our previous work on organocatalytic indole functionalization 50,51 and Morita–Baylis–Hillman (MBH) carbonate based allylation, 52–54 and inspired by Chen's N -allylic alkylation of indoles with MBH carbonates, 55 we sought to explore the reaction between Trp and MBH carbonates to develop a novel strategy for peptide functionalization.…”

Michael Addition Reaction between Dehydroalanines and Phosphites Enabled the Introduction of Phosphonates into Oligopeptides

“…In line with our recent late-stage peptide modification efforts, − including those based on Dha, − and antimicrobial peptide development, − we sought to develop a rapid and facile method for peptide phosphorylation using the P Michael addition of readily available phosphites to the Dha residue, which would be a novel strategy for the screening of potential antimicrobial phosphopeptide hits (Scheme B).…”