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Abstract
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 amino acid residue.
Original language | English |
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Pages (from-to) | 2066-2074 |
Number of pages | 9 |
Journal | Bioorganic & Medicinal Chemistry |
Volume | 27 |
Issue number | 10 |
Early online date | 3 Apr 2019 |
DOIs | |
Publication status | Published - 15 May 2019 |
Keywords
- Covalent drug
- Reactivity
- Warhead
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Projects
- 1 Active
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Wellcome Centre for Anti-Infectives Research
Cook, S., Fairlamb, A., Ferguson, M., Field, M., Gilbert, I., Gray, D., Horn, D., Read, K. & Wyatt, P.
1/04/17 → 31/03/22
Project: Research