TY - JOUR
T1 - Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L
AU - Sacco, Michael Dominic
AU - Ma, Chunlong
AU - Lagarias, Panagiotis
AU - Gao, Ang
AU - Townsend, Julia Alma
AU - Meng, Xiangzhi
AU - Dube, Peter
AU - Zhang, Xiujun
AU - Hu, Yanmei
AU - Kitamura, Naoya
AU - Hurst, Brett
AU - Tarbet, Bart
AU - Marty, Michael Thomas
AU - Kolocouris, Antonios
AU - Xiang, Yan
AU - Chen, Yu
AU - Wang, Jun
N1 - Funding Information:
This research was partially supported by the NIH (grants AI147325 and AI157046) and the Arizona Biomedical Research Centre Young Investigator grant (ADHS18-198859) to J.W. J.A.T. and M.T.M. were funded by the National Institute of General Medical Sciences and NIH (grant R35 GM128624 to M.T.M.). Y.X. was funded by the NIH (grant AI151638). The SARS-CoV-2 experiments were supported by a COVID-19 pilot grant from UTHSCSA to Y.X.
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/12/9
Y1 - 2020/12/9
N2 - The main protease (Mpro) of SARS-CoV-2 is a key antiviral drug target. While most Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of Mpro in complex with calpain inhibitors II and XII and three analogs of GC-376. The structure of Mpro with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.
AB - The main protease (Mpro) of SARS-CoV-2 is a key antiviral drug target. While most Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of Mpro in complex with calpain inhibitors II and XII and three analogs of GC-376. The structure of Mpro with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.
UR - http://www.scopus.com/inward/record.url?scp=85097930636&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097930636&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abe0751
DO - 10.1126/sciadv.abe0751
M3 - Article
C2 - 33158912
AN - SCOPUS:85097930636
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 50
M1 - eabe0751
ER -