An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo

2024/11/01 by Nian Zhou, Su Tang, Xuelin Bian +29 · 1 voice · 1 citation
Medicine · #Influenza Virus Research Studies #SARS-CoV-2 and COVID-19 Research #Viral gastroenteritis research and epidemiology

paper · doi:10.1016/j.celrep.2024.114929

openalex publication_date 2024/11/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23

Abstract

Safe, 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 μM IC 50 ) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM 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.

Citations

• Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors
• Remdesivir for the Treatment of Covid-19 — Final Report
• UCSF ChimeraX: Structure visualization for researchers, educators, and developers
• Coronavirus biology and replication: implications for SARS-CoV-2
• The WHO estimates of excess mortality associated with the COVID-19 pandemic
• The CCP 4 suite: integrative software for macromolecular crystallography

Cited by

• C6-Alkoxy substituted penicillins are potent non-covalently binding inhibitors of the SARS-CoV-2 main protease

Discussions

• Tierstudie zu neuem antiviralen Wirkstoff NZ-804 "An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo" doi.org/10.1016/j.ce... #TeamVo [bsky, 7 points, 1 comments]

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