Keriann M. Backus
Current Topics in Microbiology and Immunology book series, 2018
Cysteine thiols are involved in a diverse set of biological transformations, including nucleophilic and redox catalysis, metal coordination and formation of both dynamic and structural disulfides. Often posttranslationally modified, cysteines are also frequently alkylated by electrophilic compounds, including electrophilic metabolites, drugs, and natural products, and are attractive sites for covalent probe and drug development. Quantitative proteomics combined with activity-based protein profiling has been applied to annotate cysteine reactivity, susceptibility to posttranslational modifications, and accessibility to chemical probes, uncovering thousands of functional and small-molecule targetable cysteines across a diverse set of proteins, proteome-wide in an unbiased manner. Reactive cysteines have been targeted by high-throughput screening and fragment-based ligand discovery efforts. New cysteine-reactive electrophiles and compound libraries have been synthesized to enable inhibitor discovery broadly and to minimize nonspecific toxicity and off-target activity of compounds. With the recent blockbuster success of several covalent inhibitors, and the development of new chemical proteomic strategies to broadly identify reactive, ligandable and posttranslationally modified cysteines, cysteine profiling is poised to enable the development of new potent and selective chemical probes and even, in some cases, new drugs.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter and @firstname.lastname@example.org on Mastodon
Thursday, August 23, 2018
Applications of Reactive Cysteine Profiling
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...