8w1t | pdb_00008w1t
SARS-CoV-2 Main protease bound to a non-covalent non-peptidic HTS hit
Structural highlights
Publication Abstract from PubMedSafe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry. NZ-804 potently inhibits SARS-CoV-2 Mpro (0.009 muM IC(50)) as well as SARS-CoV-2 replication in human lung cell lines (0.008 muM EC(50)) and primary human airway epithelial cell cultures. Antiviral activity is maintained against distantly related sarbecoviruses and endemic human CoV OC43. In SARS-CoV-2 mouse and hamster disease models, NZ-804 therapy given once or twice daily significantly diminished SARS-CoV-2 replication and pathogenesis. NZ-804 synthesis is low cost and uncomplicated, simplifying global production and access. These data support the exploration of NZ-804 as a therapy for COVID-19 and future emerging sarbecovirus infections. An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.,Zhou NE, Tang S, Bian X, Parai MK, Krieger IV, Flores A, Jaiswal PK, Bam R, Wood JL, Shi Z, Stevens LJ, Scobey T, Diefenbacher MV, Moreira FR, Baric TJ, Acharya A, Shin J, Rathi MM, Wolff KC, Riva L, Bakowski MA, McNamara CW, Catanzaro NJ, Graham RL, Schultz DC, Cherry S, Kawaoka Y, Halfmann PJ, Baric RS, Denison MR, Sheahan TP, Sacchettini JC Cell Rep. 2024 Nov 5;43(11):114929. doi: 10.1016/j.celrep.2024.114929. PMID:39504242[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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