James S. Martin, Claire J. MacKenzie, Daniel Fletcher, Ian H. Gilbert,
Bioorganic & Medicinal Chemistry,
2019, DOI: 10.1016/j.bmc.2019.04.002
Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine - the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the residue.
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
Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30
Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka & Malte Gersch Nat Struct Mol Biol , 2025 https://doi.org/10.1038/s415...
-
DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
-
Özge Ünsal, Z. Selin Bacaksiz, Vladislav Khamraev, Vittorio Montanari, Martin Beinborn, and Krishna Kumar ACS Chemical Biology 2024 DOI: ...
-
Klett, T., Schwer, M., Ernst, L. N., Engelhardt, M. U., Jaag, S. J., Masberg, B., … Boeckler, F. M. Drug Design, Development and Therapy, 20...