tetano
Editor, Senior Moderator
Cell Rep
. 2024 Nov 5;43(11):114929.
doi: 10.1016/j.celrep.2024.114929. Online ahead of print. An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo
Nian E Zhou[SUP] 1 [/SUP], Su Tang[SUP] 1 [/SUP], Xuelin Bian[SUP] 1 [/SUP], Maloy K Parai[SUP] 1 [/SUP], Inna V Krieger[SUP] 1 [/SUP], Armando Flores[SUP] 1 [/SUP], Pradeep K Jaiswal[SUP] 1 [/SUP], Radha Bam[SUP] 1 [/SUP], Jeremy L Wood[SUP] 1 [/SUP], Zhe Shi[SUP] 1 [/SUP], Laura J Stevens[SUP] 2 [/SUP], Trevor Scobey[SUP] 3 [/SUP], Meghan V Diefenbacher[SUP] 3 [/SUP], Fernando R Moreira[SUP] 3 [/SUP], Thomas J Baric[SUP] 3 [/SUP], Arjun Acharya[SUP] 1 [/SUP], Joonyoung Shin[SUP] 1 [/SUP], Manish M Rathi[SUP] 1 [/SUP], Karen C Wolff[SUP] 4 [/SUP], Laura Riva[SUP] 4 [/SUP], Malina A Bakowski[SUP] 4 [/SUP], Case W McNamara[SUP] 4 [/SUP], Nicholas J Catanzaro[SUP] 3 [/SUP], Rachel L Graham[SUP] 3 [/SUP], David C Schultz[SUP] 5 [/SUP], Sara Cherry[SUP] 6 [/SUP], Yoshihiro Kawaoka[SUP] 7 [/SUP], Peter J Halfmann[SUP] 7 [/SUP], Ralph S Baric[SUP] 8 [/SUP], Mark R Denison[SUP] 2 [/SUP], Timothy P Sheahan[SUP] 9 [/SUP], James C Sacchettini[SUP] 10 [/SUP]
Affiliations
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[SUB]50[/SUB]) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC[SUB]50[/SUB]) 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.
Keywords: CP: Microbiology; Paxlovid; SARS-CoV-2; antiviral; broad-spectrum; coronavirus; emerging viruses; protease; therapeutics.
. 2024 Nov 5;43(11):114929.
doi: 10.1016/j.celrep.2024.114929. Online ahead of print. An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo
Nian E Zhou[SUP] 1 [/SUP], Su Tang[SUP] 1 [/SUP], Xuelin Bian[SUP] 1 [/SUP], Maloy K Parai[SUP] 1 [/SUP], Inna V Krieger[SUP] 1 [/SUP], Armando Flores[SUP] 1 [/SUP], Pradeep K Jaiswal[SUP] 1 [/SUP], Radha Bam[SUP] 1 [/SUP], Jeremy L Wood[SUP] 1 [/SUP], Zhe Shi[SUP] 1 [/SUP], Laura J Stevens[SUP] 2 [/SUP], Trevor Scobey[SUP] 3 [/SUP], Meghan V Diefenbacher[SUP] 3 [/SUP], Fernando R Moreira[SUP] 3 [/SUP], Thomas J Baric[SUP] 3 [/SUP], Arjun Acharya[SUP] 1 [/SUP], Joonyoung Shin[SUP] 1 [/SUP], Manish M Rathi[SUP] 1 [/SUP], Karen C Wolff[SUP] 4 [/SUP], Laura Riva[SUP] 4 [/SUP], Malina A Bakowski[SUP] 4 [/SUP], Case W McNamara[SUP] 4 [/SUP], Nicholas J Catanzaro[SUP] 3 [/SUP], Rachel L Graham[SUP] 3 [/SUP], David C Schultz[SUP] 5 [/SUP], Sara Cherry[SUP] 6 [/SUP], Yoshihiro Kawaoka[SUP] 7 [/SUP], Peter J Halfmann[SUP] 7 [/SUP], Ralph S Baric[SUP] 8 [/SUP], Mark R Denison[SUP] 2 [/SUP], Timothy P Sheahan[SUP] 9 [/SUP], James C Sacchettini[SUP] 10 [/SUP]
Affiliations
- PMID: 39504242
- DOI: 10.1016/j.celrep.2024.114929
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[SUB]50[/SUB]) as well as SARS-CoV-2 replication in human lung cell lines (0.008 μM EC[SUB]50[/SUB]) 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.
Keywords: CP: Microbiology; Paxlovid; SARS-CoV-2; antiviral; broad-spectrum; coronavirus; emerging viruses; protease; therapeutics.