7LYI

Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAWJ9-36-3

Summary for 7LYI

• Entry DOI: 10.2210/pdb7lyi/pdb
• Descriptor: 3C-like proteinase, GLYCEROL, SODIUM ION, ... (5 entities in total)
• Functional Keywords: mpro, inhibitor, main protease, 3cl, sars, sars-cov-2, covid, covid-19, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 34639.48

Authors

Sacco, M.,Wang, J.,Chen, Y. (deposition date: 2021-03-07, release date: 2021-03-17, Last modification date: 2024-10-23)

Primary citation

Xia, Z.,Sacco, M.,Hu, Y.,Ma, C.,Meng, X.,Zhang, F.,Szeto, T.,Xiang, Y.,Chen, Y.,Wang, J.
Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir.
Acs Pharmacol Transl Sci, 4:1408-1421, 2021

PubMed Abstract: SARS-CoV-2 main protease (M) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated antiviral drug target. M is highly conserved among all seven human coronaviruses, with certain M inhibitors having broad-spectrum antiviral activity. In this study, we designed two hybrid inhibitors and based on the superimposed X-ray crystal structures of SARS-CoV-2 M with GC-376, telaprevir, and boceprevir. Both and showed potent binding and enzymatic inhibition against the M's from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP M assay results show that and inhibited the intracellular protease activity of SARS-CoV-2 M. In addition, and had potent antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that and had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and cathepsin L, but not cathepsin K. The X-ray crystal structures of SARS-CoV-2 M with and were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors and are promising candidates to be further developed as broad-spectrum coronavirus antivirals.

PubMed: 34414360
DOI: 10.1021/acsptsci.1c00099

Experimental method

X-RAY DIFFRACTION (1.9 Å)