A Chemoselective Conjugation of Peptides with Electron-Rich (Hetero)Arenes

Key words

bioconjugation - protein functionalization - selenocysteine conjugation - bioorthogonal chemistry - late-stage functionalization - natural product functionalization

Significance

The site-selective functionalization of peptides with small molecules is a formidable challenge in organic synthesis. Cohen, Pentelute, and co-workers have described a new high-yielding conjugation reaction between electron-rich aromatics and of 2-thiol-5-nitropyridine (TNP)-protected selenocysteine. This methodology is an ­important advance in the production of homo­genously functionalized proteins such as antibody–drug conjugates.

Comment

A range of unprotected pharmaceutical agents and natural products are competent substrates, as demonstrated by the syntheses of vancomycin–peptide conjugates and a homogenous genistein–trastuzumab conjugate, generated by a two-step selenocysteine ligation–sortagging sequence. In general, electron-rich arenes with acidic N–H or O–H bonds are the most efficient substrates. CuSO₄ and a bipy ligand can be used to promote the reaction with less reactive arenes.