Arylfluorosulfate-Based Electrophiles for Covalent Protein Labeling: A New Addition to the Arsenal

TY - JOUR

T1 - Arylfluorosulfate-Based Electrophiles for Covalent Protein Labeling

T2 - A New Addition to the Arsenal

AU - Martín-Gago, Pablo

AU - Olsen, Christian A.

PY - 2019/1/21

Y1 - 2019/1/21

N2 - Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off-target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context-specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery.

AB - Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off-target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context-specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery.

KW - covalent inhibitors

KW - drug design

KW - electrophilic warheads

KW - medicinal chemistry

KW - protein modifications

UR - http://www.scopus.com/inward/record.url?scp=85055571883&partnerID=8YFLogxK

U2 - 10.1002/anie.201806037

DO - 10.1002/anie.201806037

M3 - Review

C2 - 30024079

AN - SCOPUS:85055571883

SN - 1433-7851

VL - 58

SP - 957

EP - 966

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 4

ER -