Abstract
The main protease (Mpro) is a validated antiviral drug target of SARS-CoV-2. A number of Mpro inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L. In this study we describe the rational design of covalent SARS-CoV-2 Mpro inhibitors with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, and 2-chloro-2,2-dibromoacetamide. The promising lead candidates Jun9-62-2R (dichloroacetamide) and Jun9-88-6R (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to GC-376, these new compounds did not inhibit the host cysteine proteases including calpain I, cathepsin B, cathepsin K, cathepsin L, and caspase-3. To the best of our knowledge, they are among the most selective covalent Mpro inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 Mpro with Jun9-62-2R and Jun9-57-3R reaffirmed our design hypothesis, showing that both compounds form a covalent adduct with the catalytic C145. Overall, these novel compounds represent valuable chemical probes for target validation and drug candidates for further development as SARS-CoV-2 antivirals.
Original language | English (US) |
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Pages (from-to) | 20697-20709 |
Number of pages | 13 |
Journal | Journal of the American Chemical Society |
Volume | 143 |
Issue number | 49 |
DOIs | |
State | Published - Dec 15 2021 |
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry
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Dive into the research topics of 'Discovery of Di- And Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity'. Together they form a unique fingerprint.Datasets
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Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun9-57-3R
Ma, C. (Contributor), Xia, Z. (Contributor), Sacco, M. D. (Contributor), Hu, Y. (Contributor), Townsend, J. A. (Contributor), Meng, X. (Contributor), Choza, J. (Contributor), Tan, H. (Contributor), Jang, J. (Contributor), Gongora, M. V. (Contributor), Zhang, X. (Contributor), Zhang, F. (Contributor), Xiang, Y. (Contributor), Marty, M. T. (Contributor), Chen, Y. (Contributor) & Wang, J. (Contributor), Protein Data Bank (PDB), Aug 11 2021
DOI: 10.2210/pdb7RN0/pdb, https://www.wwpdb.org/pdb?id=pdb_00007rn0
Dataset
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Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun9-62-2R
Ma, C. (Contributor), Xia, Z. (Contributor), Sacco, M. D. (Contributor), Hu, Y. (Contributor), Townsend, J. A. (Contributor), Meng, X. (Contributor), Choza, J. (Contributor), Tan, H. (Contributor), Jang, J. (Contributor), Gongora, M. V. (Contributor), Zhang, X. (Contributor), Zhang, F. (Contributor), Xiang, Y. (Contributor), Marty, M. T. (Contributor), Chen, Y. (Contributor) & Wang, J. (Contributor), Protein Data Bank (PDB), Sep 8 2021
DOI: 10.2210/pdb7RN1/pdb, https://www.wwpdb.org/pdb?id=pdb_00007rn1
Dataset