Alfred Tuley and Walter Fast
Biochemistry, 2018
DOI: 10.1021/acs.biochem.8b00315
Covalent enzyme inhibitors are widely applied as biochemical tools and therapeutic agents. As a complement to categorization of these inhibitors by reactive group or modification site, we present a categorization by mechanism, which highlights common advantages and disadvantages inherent to each approach. Established categories for reversible and irreversible covalent inhibition are reviewed with representative examples given for each class, including covalent reversible inhibitors, slow substrates, residue-specific reagents, affinity labels (classical, quiescent, and photoaffinity), and mechanism-based inactivators. The relationships of these categories to proteomic profiling probes (activity-based and reactivity-based) as well as complementary approaches such as prodrug and soft drug design are also discussed. A wide variety of strategies are used to balance reactivity and selectivity in the design of covalent enzyme inhibitors. Use of a shared terminology is encouraged to clearly convey these mechanisms, to relate them to prior use of covalent inhibitors in enzymology, and to facilitate the development of more effective covalent inhibitors.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders
Nathanael Schiander Gray , Zhe Zhuang , Woong Sub Byun , Zuzanna Kozicka , Katherine Donovan , Brendan Dwyer , Abby Thornhill , Hanna...
-
Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitorDandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Jo...
-
DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
-
George S. Biggs, Emma E. Cawood, Aini Vuorinen, William J. McCarthy, Harry Wilders, Ioannis G. Riziotis, Antonie J. van der Zouwen, Jonathan...