There’s a really cool class of inhibitors that’s gaining traction – reversible covalent inhibitors. They form covalent bonds but “vulnerable” ones. Basically there’s a part of the inhibitor that’s like a “normal” inhibitor – often a competitive one that binds in the active site through non-covalent interactions. That lets it get its foot in the door and provides good specificity. But then there’s a chemical “warhead” part that will react covalently to a residue in the binding site – often a lysine or a cysteine, which, because of their nucleophilicity, can attack electrophilic warheads like aldehyde groups. These bonds, although covalent, are reversible. They can break, typically through hydrolysis. But they allow the inhibitor to stay on longer than normal reversible inhibitors. And because they require that interacting protein residue to be in a precise spot, they offer high specificity for the covalent binding step (even if the non-covalent part isn’t totally specific). I think this is a really cool topic. I don’t have much text but just wanted to talk about it & share some resources…

more on classical inhibitors in yesterday’s post: http://bit.ly/enzymeinhibition     

An example of a reversible covalent inhibitor I’ve discussed before is Paxlovid: https://bit.ly/paxlovidMPro 

Here’s another example – a sickle cell anemia drug voxelotor (Oxbryta), which bonds to the N-terminus of α-globin and helps stabilize hemoglobin in a state that’s less prone to forming polymers:  Metcalf B, Chuang C, Dufu K, et al. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017;8(3):321-326. Published 2017 Jan 23. https://dx.doi.org/10.1021%2Facsmedchemlett.6b00491 

Here’s a highlight piece: Stephan M. Hacker, Promising reversible protein inhibitors kept on target, Nature (news & views article): https://www.nature.com/articles/d41586-022-00692-5 

Discussing this paper: Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time. Rahi M. Reja, Wenjian Wang, Yuhan Lyu, Fredrik Haeffner, and Jianmin Gao. Journal of the American Chemical Society 2022 144 (3), 1152-115 https://doi.org/10.1021/jacs.1c12702 

There are also enzyme inhibitors that we call IRREVERSIBLE INHIBITORS – they can’t fall off – so even if you remove all the excess inhibitor so that if it were to fall out there wouldn’t be more to bind, it wouldn’t matter because it can’t fall off!  

For example, here’s Kevan Shokat’s breakthrough 2013 paper showing that a mutant form of the KRAS protein responsible for some cancers could be inhibited covalently: Ostrem, J., Peters, U., Sos, M. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). https://doi.org/10.1038/nature12796

This led to the development of irreversible covalent inhibitors for KRAS G12C

one of which, Sotorasib (AMG 510) was approved by the FDA in 2021. Here’s a webinar talking about its development (you have to be an ACS member to access though) https://www.acs.org/content/acs/en/acs-webinars/drug-discovery/sotorasib.html 

The antibiotic penicillin is an example of a special type of irreversible inhibition that’s aka “suicide inhibition” (aka “suicide inactivation” aka “mechanism-based inhibition”). In these cases, the irreversible complex is formed during the course of the normal catalysis reaction – it gets partway there and then gets stuck. These “suicide inhibitors” are similar to the competitive inhibitors in that they bind the active site and prevent the “real deal” from binding, but unlike competitive inhibitors you can’t outcompete them.  Here’s more on how penicillin works: http://bit.ly/penamp

Here’s a recent overall review article: De Vita E. 10 years into the resurgence of covalent drugs. Future Med Chem. 2021;13(2):193-210. https://dx.doi.org/10.4155%2Ffmc-2020-0236 

The antibiotic penicillin is an example of a special type of irreversible inhibition that’s aka “suicide inhibition” (aka “suicide inactivation” aka “mechanism-based inhibition”). In these cases, the irreversible complex is formed during the course of the normal catalysis reaction – it gets partway there and then gets stuck. These “suicide inhibitors” are similar to the competitive inhibitors in that they bind the active site and prevent the “real deal” from binding, but unlike competitive inhibitors you can’t outcompete them.  Here’s more on how penicillin works: http://bit.ly/penamp 

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