8SKH

Co-structure of SARS-CoV-2 (COVID-19 with covalent pyrazoline based inhibitors

Summary for 8SKH

• Entry DOI: 10.2210/pdb8skh/pdb
• Descriptor: 3C-like proteinase nsp5, 2-chloro-1-[(4R,5R)-3,4,5-triphenyl-4,5-dihydro-1H-pyrazol-1-yl]ethan-1-one (3 entities in total)
• Functional Keywords: sars2, mpro, inhibitor, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34200.41

Authors

Knapp, M.S.,Ornelas, E. (deposition date: 2023-04-19, release date: 2023-06-07, Last modification date: 2024-10-23)

Primary citation

Moon, P.,Zammit, C.M.,Shao, Q.,Dovala, D.,Boike, L.,Henning, N.J.,Knapp, M.,Spradlin, J.N.,Ward, C.C.,Wolleb, H.,Fuller, D.,Blake, G.,Murphy, J.P.,Wang, F.,Lu, Y.,Moquin, S.A.,Tandeske, L.,Hesse, M.J.,McKenna, J.M.,Tallarico, J.A.,Schirle, M.,Toste, F.D.,Nomura, D.K.
Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors.
Chembiochem, 24:e202300116-e202300116, 2023

PubMed Abstract: While vaccines and antivirals are now being deployed for the current SARS-CoV-2 pandemic, we require additional antiviral therapeutics to not only effectively combat SARS-CoV-2 and its variants, but also future coronaviruses. All coronaviruses have relatively similar genomes that provide a potential exploitable opening to develop antiviral therapies that will be effective against all coronaviruses. Among the various genes and proteins encoded by all coronaviruses, one particularly "druggable" or relatively easy-to-drug target is the coronavirus Main Protease (3CL or Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity-based protein profiling (ABPP)-based chemoproteomic approaches to discover and further optimize cysteine-reactive pyrazoline-based covalent inhibitors for the SARS-CoV-2 Mpro. Structure-guided medicinal chemistry and modular synthesis of di- and tri-substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine-reactive warheads enabled the expedient exploration of structure-activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS-CoV-2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan-coronavirus inhibitors.

PubMed: 37069799
DOI: 10.1002/cbic.202300116

Experimental method

X-RAY DIFFRACTION (1.882 Å)