Abstract

We report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.

The essential SARS-CoV-2 3CL protease is of interest as a drug target. Here, the authors identify three 3CL inhibitors and characterize them both in vitro and with a cell-based assay, and they also present the inhibitor-bound 3CL crystal structures, which may allow for the design of improved compounds.

Details

Title
Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors
Author
Iketani Sho 1   VIAFID ORCID Logo  ; Forouhar Farhad 2 ; Liu Hengrui 3   VIAFID ORCID Logo  ; Hong Seo Jung 4 ; Fang-Yu, Lin 5   VIAFID ORCID Logo  ; Nair, Manoj S 6   VIAFID ORCID Logo  ; Zask Arie 7 ; Huang Yaoxing 6   VIAFID ORCID Logo  ; Li, Xing 5   VIAFID ORCID Logo  ; Stockwell, Brent R 8   VIAFID ORCID Logo  ; Chavez, Alejandro 4   VIAFID ORCID Logo  ; Ho, David D 1   VIAFID ORCID Logo 

1  Columbia University Irving Medical Center, Aaron Diamond AIDS Research Center, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Columbia University Irving Medical Center, Department of Microbiology and Immunology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
2  Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
3  Columbia University, Department of Chemistry, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
4  Columbia University Irving Medical Center, Department of Pathology and Cell Biology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
5  WuXi AppTec, Cambridge, USA (GRID:grid.21729.3f) 
6  Columbia University Irving Medical Center, Aaron Diamond AIDS Research Center, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
7  Columbia University, Department of Biological Sciences, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
8  Columbia University, Department of Chemistry, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Columbia University, Department of Biological Sciences, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-22362-2
ProQuest document ID
2507805908
Copyright
© The Author(s) 2021. corrected publication 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.