8R7B

SARS-CoV-2 NSP14 in complex with SAH and TDI-015051

Summary for 8R7B

• Entry DOI: 10.2210/pdb8r7b/pdb
• Descriptor: Guanine-N7 methyltransferase nsp14, ZINC ION, S-ADENOSYL-L-HOMOCYSTEINE, ... (8 entities in total)
• Functional Keywords: nsp14, sars-cov-2, methyltransferase, viral protein, inhibitor complex
• Biological source: SARS-CoV-2 pseudovirus
• Total number of polymer chains: 2
• Total formula weight: 122526.09

Authors

Meyer, C.,Garzia, A.,Miller, M.,Huggins, D.J.,Myers, R.W.,Liverton, N.,Kargman, S.,Nitsche, J.,Ganichkin, O.,Steinbacher, S.,Meinke, P.T.,Tuschl, T. (deposition date: 2023-11-24, release date: 2024-10-23, Last modification date: 2025-02-05)

Primary citation

Meyer, C.,Garzia, A.,Miller, M.W.,Huggins, D.J.,Myers, R.W.,Hoffmann, H.H.,Ashbrook, A.W.,Jannath, S.Y.,Liverton, N.,Kargman, S.,Zimmerman, M.,Nelson, A.M.,Sharma, V.,Dolgov, E.,Cangialosi, J.,Penalva-Lopez, S.,Alvarez, N.,Chang, C.W.,Oswal, N.,Gonzalez, I.,Rasheed, R.,Goldgirsh, K.,Davis, J.A.,Ramos-Espiritu, L.,Menezes, M.R.,Larson, C.,Nitsche, J.,Ganichkin, O.,Alwaseem, H.,Molina, H.,Steinbacher, S.,Glickman, J.F.,Perlin, D.S.,Rice, C.M.,Meinke, P.T.,Tuschl, T.
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase.
Nature, 637:1178-1185, 2025

PubMed Abstract: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid development of highly effective vaccines against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics 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. 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) of 61 pM and a half-maximal effective concentration (EC) 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. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.

PubMed: 39663451
DOI: 10.1038/s41586-024-08320-0

Experimental method

X-RAY DIFFRACTION (2.18 Å)