9L09

SARS-CoV-2 C-RTC with 13-TP

This is a non-PDB format compatible entry.

Summary for 9L09

• Entry DOI: 10.2210/pdb9l09/pdb
• EMDB information: 62692
• Descriptor: RNA-directed RNA polymerase nsp12, Non-structural protein 8, Non-structural protein 7, ... (8 entities in total)
• Functional Keywords: sars-cov-2 c-rtc, viral protein/rna, viral protein-rna complex
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 6
• Total formula weight: 167022.57

Authors

Huang, Y.C.,Liang, L.,Liu, Y.X.,Yan, L.M.,Lou, Z.Y.,Rao, Z.H. (deposition date: 2024-12-12, release date: 2025-03-19, Last modification date: 2025-03-26)

Primary citation

Liang, L.,Meng, Y.,Chang, X.,Li, E.,Huang, Y.,Yan, L.,Lou, Z.,Peng, Y.,Zhu, B.,Yu, W.,Chang, J.
Discovery of a 2'-a-Fluoro-2'-b-C-(fluoromethyl) Purine Nucleotide Prodrug as a Potential Oral Anti-SARS-CoV-2 Agent
J Med Chem, 68:1994-2007, 2025

PubMed Abstract: A novel 2'-α-fluoro-2'-β--(fluoromethyl) purine nucleoside phosphoramidate prodrug has been designed and synthesized to treat SARS-CoV-2 infection. The SARS-CoV-2 central replication transcription complex (C-RTC, nsp12-nsp7-nsp8) catalyzed in vitro RNA synthesis was effectively inhibited by the corresponding bioactive nucleoside triphosphate (). The cryo-electron microscopy structure of the C-RTC: complex was also determined. Compound exhibited potent in vitro antiviral activity against the SARS-CoV-2 20SF107 strain (EC = 0.56 ± 0.06 μM) and the Omicron BA.5 variant (EC = 0.96 ± 0.23 μM) with low cytotoxicity. Furthermore, it was well tolerated in rats at doses of up to 2000 mg/kg, and a single oral dose of this prodrug at 40 mg/kg led to high levels of in the target organ lungs of rats with a long half-life. These findings support the further development of compound as an orally available antiviral agent for the treatment of SARS-CoV-2 infection.

PubMed: 39804580
DOI: 10.1021/acs.jmedchem.4c02769

Experimental method

ELECTRON MICROSCOPY (2.9 Å)