TY - JOUR
T1 - Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors
AU - Kitamura, Naoya
AU - Sacco, Michael Dominic
AU - Ma, Chunlong
AU - Hu, Yanmei
AU - Townsend, Julia Alma
AU - Meng, Xiangzhi
AU - Zhang, Fushun
AU - Zhang, Xiujun
AU - Ba, Mandy
AU - Szeto, Tommy
AU - Kukuljac, Adis
AU - Marty, Michael Thomas
AU - Schultz, David
AU - Cherry, Sara
AU - Xiang, Yan
AU - Chen, Yu
AU - Wang, Jun
N1 - Funding Information:
This research was partially supported by the National Institutes of Health (NIH) (Grants AI147325 and AI157046) and the Arizona Biomedical Research Centre Young Investigator grant (ADHS18-198859) to J.W. The antiviral assay in Calu-3 cells was conducted through the NIAID preclinical service under a nonclinical evaluation agreement. J.A.T. and M.T.M. were funded by the National Institute of General Medical Sciences and National Institutes of Health (Grant R35 GM128624 to M.T.M.). We thank Michael Kemp for assistance with crystallization and X-ray diffraction data collection. We also thank the staff members of the Advanced Photon Source of Argonne National Laboratory, particularly those at the Structural Biology Center (SBC), with X-ray diffraction data collection. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. The SARS-CoV-2 experiments were supported by a COVID-19 pilot grant from UTHSCSA and NIH grant AI151638 to Y.X. SARS-Related Coronavirus 2, Isolate USA-WA1/2020 (NR-52281) was deposited by the Centers for Disease Control and Prevention and obtained through BEI Resources, NIAID, NIH.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2022/2/24
Y1 - 2022/2/24
N2 - The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro 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 Mpro 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 Mpro 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 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.
AB - The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro 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 Mpro 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 Mpro 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 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.
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U2 - 10.1021/acs.jmedchem.1c00509
DO - 10.1021/acs.jmedchem.1c00509
M3 - Article
C2 - 33891389
AN - SCOPUS:85106487174
VL - 65
SP - 2848
EP - 2865
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 4
ER -