Abstract
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.
Original language | English (US) |
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Article number | eabe0751 |
Journal | Science Advances |
Volume | 6 |
Issue number | 50 |
DOIs | |
State | Published - Dec 9 2020 |
ASJC Scopus subject areas
- General
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Dive into the research topics of 'Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L'. 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 UAW243
Sacco, M. D. (Contributor), Ma, C. (Contributor), Lagarias, P. (Contributor), Gao, A. (Contributor), Townsend, J. A. (Contributor), Meng, X. (Contributor), Dube, P. (Contributor), Zhang, X. (Contributor), Hu, Y. (Contributor), Kitamura, N. (Contributor), Hurst, B. (Contributor), Tarbet, B. (Contributor), Marty, M. T. (Contributor), Kolocouris, A. (Contributor), Xiang, Y. (Contributor), Chen, Y. (Contributor) & Wang, J. (Contributor), Protein Data Bank (PDB), Jun 24 2020
DOI: 10.2210/pdb6XFN/pdb, https://www.wwpdb.org/pdb?id=pdb_00006xfn
Dataset
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Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAW247
Sacco, M. D. (Contributor), Ma, C. (Contributor), Lagarias, P. (Contributor), Gao, A. (Contributor), Townsend, J. A. (Contributor), Meng, X. (Contributor), Dube, P. (Contributor), Zhang, X. (Contributor), Hu, Y. (Contributor), Kitamura, N. (Contributor), Hurst, B. (Contributor), Tarbet, B. (Contributor), Marty, M. T. (Contributor), Kolocouris, A. (Contributor), Xiang, Y. (Contributor), Chen, Y. (Contributor) & Wang, J. (Contributor), Protein Data Bank (PDB), Jun 17 2020
DOI: 10.2210/pdb6XBH/pdb, https://www.wwpdb.org/pdb?id=pdb_00006xbh
Dataset
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Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAW248
Sacco, M. D. (Contributor), Ma, C. (Contributor), Lagarias, P. (Contributor), Gao, A. (Contributor), Townsend, J. A. (Contributor), Meng, X. (Contributor), Dube, P. (Contributor), Zhang, X. (Contributor), Hu, Y. (Contributor), Kitamura, N. (Contributor), Hurst, B. (Contributor), Tarbet, B. (Contributor), Marty, M. T. (Contributor), Kolocouris, A. (Contributor), Xiang, Y. (Contributor), Chen, Y. (Contributor) & Wang, J. (Contributor), Protein Data Bank (PDB), Jun 17 2020
DOI: 10.2210/pdb6XBI/pdb, https://www.wwpdb.org/pdb?id=pdb_00006xbi
Dataset