Journal
STRUCTURE
Volume 29, Issue 8, Pages 823-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2021.06.002
Keywords
-
Funding
- US National Institutes of Health (NIH) [GM32136, AI087925, R35 GM132092, T32GM136651]
- CoReCT Pilot Grant from the Yale University School of Medicine
- NSF Graduate Research Fellowship Program
- DOE Office of Science [DE-SC0012704, DE-AC02-06CH11357]
- NIH, National Institute of General Medical Sciences (NIGMS) [P30GM133893]
- DOE Office of Biological and Environmental Research [KP1605010]
- NIGMS from the NIH [P30 GM124165]
- NIH-ORIP HEI grant [S10OD021527]
Ask authors/readers for more resources
This study optimized an existing FDA-approved chemical scaffold, perampanel, to noncovalently bind and inhibit M-pro, achieving IC(50)s in the low-nanomolar range and EC(50)s in the low-micromolar range. The research presented nine crystal structures of Mpro bound to a series of perampanel analogs, providing detailed structural insights into their mechanism of action and structure-activity relationship. These insights reveal strategies for rational inhibitor design efforts in the context of active-site flexibility and potential resistance mechanisms.
There is a clinical need for direct-acting antivirals targeting SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, to complement current therapeutic strategies. The main protease (M-pro) is an attractive target for antiviral therapy. However, the vast majority of protease inhibitors described thus far are peptidomimetic and bind to the active-site cysteine via a covalent adduct, which is generally pharmacokinetically unfavorable. We have reported the optimization of an existing FDA-approved chemical scaffold, perampanel, to bind to and inhibit M-pro noncovalently with IC(50)s in the low-nanomolar range and EC(50)s in the low-micromolar range. Here, we present nine crystal structures of Mpro bound to a series of perampanel analogs, providing detailed structural insights into their mechanism of action and structure-activity relationship. These insights further reveal strategies for pursuing rational inhibitor design efforts in the context of considerable active-site flexibility and potential resistance mechanisms.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available