Sulfinate Salts Enable Late-Stage, Residue-Specific Modification of Peptide Disulfide Bonds via Umpolung Chemistry

Peptide modification is crucial for tailoring structure and function, yet current methods often rely on the nucleophilicity of cysteine thiols. This approach limits the scope of modifications and can be challenging for late-stage functionalization of complex peptides. The electrophilicity of the cystine disulfide bond, an 'umpolung' strategy, remains largely underexplored, representing a significant gap in peptide chemistry for creating diverse and high-value peptide therapeutics with enhanced properties.

Researchers developed and optimized a mild, photochemical strategy utilizing sulfinate salts to generate carbon-centered radicals. This method was applied to both symmetrical and electronically-distinct, unsymmetrical cystine disulfides. High-throughput experimentation (HTE) techniques were employed to optimize reaction conditions and investigate the matched reactivity of specific radical/disulfide substrate pairings. The compatibility of the method was tested across a range of unprotected amino acids, including histidine, tryptophan, and tyrosine, and demonstrated on a semaglutide analogue and for the preparation of macrocyclic peptides.

The novel photochemical strategy successfully enabled the late-stage modification of peptidic disulfide bonds using sulfinate salts. A diverse library of modified peptides was readily accessible, with successful modification confirmed by both qualitative and quantitative analytical data. The method demonstrated broad compatibility with various unprotected amino acids, including histidine, tryptophan, and tyrosine, without requiring protecting groups. This indicates high selectivity for the disulfide bond. The approach provided valuable insights into the specific reactivity pairings between radicals and disulfide substrates. > The method was effectively applied to the selective, late-stage functionalization of a semaglutide analogue, showcasing its potential for modifying biologically relevant peptides and facilitating the preparation of high-value macrocyclic peptides.