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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
The main protease (M(pro)) of SARS-CoV-2 is a validated antiviral drug target. Several M(pro) inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II, and XII, with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, 23R (Jun8-76-3A) that is structurally distinct from the canonical M(pro) inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 M(pro) with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 M(pro) inhibitors reported to date, and a novel binding pocket in M(pro) that can be explored for inhibitor design.
The main protease (M(pro)) is a validated antiviral drug target of SARS-CoV-2. A number of M(pro) 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 M(pro) 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 M(pro) inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 M(pro) 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.


Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors.,Kitamura N, Sacco MD, Ma C, Hu Y, Townsend JA, Meng X, Zhang F, Zhang X, Ba M, Szeto T, Kukuljac A, Marty MT, Schultz D, Cherry S, Xiang Y, Chen Y, Wang J J Med Chem. 2021 Apr 23. doi: 10.1021/acs.jmedchem.1c00509. PMID:33891389<ref>PMID:33891389</ref>
Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.,Ma C, Xia Z, Sacco MD, Hu Y, Townsend JA, Meng X, Choza J, Tan H, Jang J, Gongora MV, Zhang X, Zhang F, Xiang Y, Marty MT, Chen Y, Wang J J Am Chem Soc. 2021 Dec 15;143(49):20697-20709. doi: 10.1021/jacs.1c08060. Epub, 2021 Dec 3. PMID:34860011<ref>PMID:34860011</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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