Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 13, Pages 6146-6162Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00387
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Funding
- National Key Research and Development Program of China [2018YFA0507204]
- National Natural Science Foundation of China [21672115, 81801998]
- Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory, Chinese Academy of Sciences [2018ACCP-MS06]
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Targeted covalent inhibitors (TCIs) have attracted growing attention from the pharmaceutical industry in recent decades because they have potential advantages in terms of efficacy, selectivity, and safety. TCIs have recently evolved into a new version with reversibility that can be systematically modulated. This feature may diminish the risk of haptenization and help optimize the drug-target residence time as needed. The enteroviral 3C protease (3C(pro)) is a valuable therapeutic target, but the development of 3C(pro) inhibitors is far from satisfactory. Therefore, we aimed to apply a reversible TCI approach to the design of novel 3C(pro) inhibitors. The introduction of various substituents onto the alpha-carbon of classical Michael acceptors yielded inhibitors bearing several classes of warheads. Using steady-state kinetics and biomolecular mass spectrometry, we confirmed the mode of reversible covalent inhibition and elucidated the mechanism by which the potency and reversibility were affected by electronic and steric factors. This research produced several potent inhibitors with good selectivity and suitable reversibility; moreover, it validated the reversible TCI approach in the field of viral infection, suggesting broader applications in the design of reversible covalent inhibitors for other proteases.
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