Cohen DT.
*
Zhang C,
Fadzen CM,
Mijalis AJ,
Hie L,
Johnson KD,
Shriver Z,
Plante O,
Miller SJ,
Buchwald SL,
Pentelute BL.
* Massachusetts Institute of Technology, Cambridge, Yale University, New Haven, and
Visterra Inc., Cambridge, USA
A Chemoselective Strategy for Late-Stage Functionalization of Complex Small Molecules
with Polypeptides and Proteins.
Nat. Chem. 2019;
11: 78-85
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.
