7RN1

Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun9-62-2R

Summary for 7RN1

• Entry DOI: 10.2210/pdb7rn1/pdb
• Descriptor: 3C-like proteinase, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: mpro, inhibitor, main protease, 3cl, sars, sars-cov-2, covid, covid-19, viral protein, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34589.79

Authors

Sacco, M.,Chen, Y. (deposition date: 2021-07-28, release date: 2021-09-08, Last modification date: 2024-10-30)

Primary citation

Ma, C.,Xia, Z.,Sacco, M.D.,Hu, Y.,Townsend, J.A.,Meng, X.,Choza, J.,Tan, H.,Jang, J.,Gongora, M.V.,Zhang, X.,Zhang, F.,Xiang, Y.,Marty, M.T.,Chen, Y.,Wang, J.
Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.
J.Am.Chem.Soc., 143:20697-20709, 2021

PubMed Abstract: The main protease (M) is a validated antiviral drug target of SARS-CoV-2. A number of M 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 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 (dichloroacetamide) and (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to , 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 inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 M with and 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.

PubMed: 34860011
DOI: 10.1021/jacs.1c08060

Experimental method

X-RAY DIFFRACTION (2.3 Å)