tetano
Editor, Senior Moderator
Nature
. 2024 Dec 11.
doi: 10.1038/s41586-024-08320-0. Online ahead of print. Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
Cindy Meyer[SUP] 1 [/SUP], Aitor Garzia[SUP] 1 [/SUP], Michael W Miller[SUP] 2 [/SUP], David J Huggins[SUP] 2 3 [/SUP], Robert W Myers[SUP] 2 [/SUP], Hans-Heinrich Hoffmann[SUP] 4 [/SUP], Alison W Ashbrook[SUP] 4 [/SUP], Syeda Y Jannath[SUP] 4 [/SUP], Nigel Liverton[SUP] 2 [/SUP], Stacia Kargman[SUP] 2 [/SUP], Matthew Zimmerman[SUP] 5 [/SUP], Andrew M Nelson[SUP] 5 [/SUP], Vijeta Sharma[SUP] 5 [/SUP], Enriko Dolgov[SUP] 5 [/SUP], Julianna Cangialosi[SUP] 5 [/SUP], Suyapa Penalva-Lopez[SUP] 5 [/SUP], Nadine Alvarez[SUP] 5 [/SUP], Ching-Wen Chang[SUP] 4 5 6 [/SUP], Neelam Oswal[SUP] 5 [/SUP], Irene Gonzalez[SUP] 5 [/SUP], Risha Rasheed[SUP] 5 [/SUP], Kira Goldgirsh[SUP] 5 [/SUP], Jada A Davis[SUP] 1 [/SUP], Lavoisier Ramos-Espiritu[SUP] 7 [/SUP], Miriam-Rose Menezes[SUP] 7 [/SUP], Chloe Larson[SUP] 7 [/SUP], Julius Nitsche[SUP] 8 [/SUP], Oleg Ganichkin[SUP] 8 [/SUP], Hanan Alwaseem[SUP] 9 [/SUP], Henrik Molina[SUP] 9 [/SUP], Stefan Steinbacher[SUP] 8 [/SUP], J Fraser Glickman[SUP] 7 [/SUP], David S Perlin[SUP] 5 [/SUP], Charles M Rice[SUP] 4 [/SUP], Peter T Meinke[SUP] 2 [/SUP], Thomas Tuschl[SUP] 10 [/SUP]
Affiliations
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[SUP]1[/SUP]. The rapid development of highly effective vaccines[SUP]2,3[/SUP] against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics[SUP]4[/SUP] have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity[SUP]5[/SUP]. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (K[SUB]d[/SUB]) of 61 pM and a half-maximal effective concentration (EC[SUB]50[/SUB]) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir[SUP]6[/SUP]. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.
. 2024 Dec 11.
doi: 10.1038/s41586-024-08320-0. Online ahead of print. Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
Cindy Meyer[SUP] 1 [/SUP], Aitor Garzia[SUP] 1 [/SUP], Michael W Miller[SUP] 2 [/SUP], David J Huggins[SUP] 2 3 [/SUP], Robert W Myers[SUP] 2 [/SUP], Hans-Heinrich Hoffmann[SUP] 4 [/SUP], Alison W Ashbrook[SUP] 4 [/SUP], Syeda Y Jannath[SUP] 4 [/SUP], Nigel Liverton[SUP] 2 [/SUP], Stacia Kargman[SUP] 2 [/SUP], Matthew Zimmerman[SUP] 5 [/SUP], Andrew M Nelson[SUP] 5 [/SUP], Vijeta Sharma[SUP] 5 [/SUP], Enriko Dolgov[SUP] 5 [/SUP], Julianna Cangialosi[SUP] 5 [/SUP], Suyapa Penalva-Lopez[SUP] 5 [/SUP], Nadine Alvarez[SUP] 5 [/SUP], Ching-Wen Chang[SUP] 4 5 6 [/SUP], Neelam Oswal[SUP] 5 [/SUP], Irene Gonzalez[SUP] 5 [/SUP], Risha Rasheed[SUP] 5 [/SUP], Kira Goldgirsh[SUP] 5 [/SUP], Jada A Davis[SUP] 1 [/SUP], Lavoisier Ramos-Espiritu[SUP] 7 [/SUP], Miriam-Rose Menezes[SUP] 7 [/SUP], Chloe Larson[SUP] 7 [/SUP], Julius Nitsche[SUP] 8 [/SUP], Oleg Ganichkin[SUP] 8 [/SUP], Hanan Alwaseem[SUP] 9 [/SUP], Henrik Molina[SUP] 9 [/SUP], Stefan Steinbacher[SUP] 8 [/SUP], J Fraser Glickman[SUP] 7 [/SUP], David S Perlin[SUP] 5 [/SUP], Charles M Rice[SUP] 4 [/SUP], Peter T Meinke[SUP] 2 [/SUP], Thomas Tuschl[SUP] 10 [/SUP]
Affiliations
- PMID: 39663451
- DOI: 10.1038/s41586-024-08320-0
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[SUP]1[/SUP]. The rapid development of highly effective vaccines[SUP]2,3[/SUP] against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics[SUP]4[/SUP] have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity[SUP]5[/SUP]. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (K[SUB]d[/SUB]) of 61 pM and a half-maximal effective concentration (EC[SUB]50[/SUB]) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir[SUP]6[/SUP]. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.