Kristine Senkane, Ekaterina Vinogradova, Radu Suciu, Vincent Crowley, Balyn Zaro, Michael Bradshaw ,Ken Brameld, Benjamin Cravatt
Angew. Chem. 2019
doi:10.1002/ange.201905829
Reversible covalency, achieved with, for instance, highly electron‐deficient olefins, offers a compelling strategy to design chemical probes and drugs that benefit from the sustained target engagement afforded by irreversible compounds, while avoiding permanent protein modification that persists following unfolding and/or proteolytic processing. So far, reversible covalency has mainly been evaluated for cysteine residues in individual kinases and the broader potential for this strategy to engage cysteines across the proteome remains unexplored. Here we describe a mass‐spectrometry‐based platform that integrates gel filtration (GF) with activity‐based protein profiling (ABPP) to assess cysteine residues across the human proteome for both irreversible and reversible interactions with small‐molecule electrophiles. Using this method, we identify numerous cysteine residues from diverse protein classes that are reversibly engaged by cyanoacrylamide fragment electrophiles, revealing the broad potential for reversible covalency as a strategy for chemical probe discovery.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @covalentmod@mstdn.science on Mastodon
Covalent drug discovery using sulfur(VI) fluoride exchange warheads
Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...
-
Zhao, Z.; Bourne, P. E. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-nlb0m Kinase-targeted drug discovery for cancer therapy ha...
-
Wang, S.; Hadisurya, M.; Tao, W. A.; Dykhuizen, E.; Krusemark, C. ChemRxiv 2022 . https://doi.org/10.26434/chemrxiv-2022-tvgn1 Targeted co...
-
Jian Ding, Guo Li, Hejun Liu, Lulu Liu, Ying Lin, Jingyan Gao, Guoqiang Zhou, Lingling Shen, Mengxi Zhao, Yanyan Yu, Weihui Guo, Ulrich Homm...