ArticleNucleic acids research2024
An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Mechanism of SARS-CoV-2 resistance to nucleotide analog-based antivirals.Nature communications · 2026Article
- 1'-Cyanocytidine-5'-isobutyryl is a potent SARS-CoV-2 inhibitor in culture and infected Syrian hamsters.Science advances · 2025Article
- Trioxane-based MS-cleavable cross-linking mass spectrometry for profiling multimeric interactions of cellular networks.Nature communications · 2025Article
- A Mini-Review on the Common Antiviral Drug Targets of Coronavirus.Microorganisms · 2024Review
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Authors and funding
12 authors.
Funding
Abstract
Nucleotide analogues (NA) are currently employed for treatment of several viral diseases, including COVID-19. NA prodrugs are intracellularly activated to the 5'-triphosphate form. They are incorporated into the viral RNA by the viral polymerase (SARS-CoV-2 nsp12), terminating or corrupting RNA synthesis. For Coronaviruses, natural resistance to NAs is provided by a viral 3'-to-5' exonuclease heterodimer nsp14/nsp10, which can remove terminal analogues. Here, we show that the replacement of the α-phosphate of Bemnifosbuvir 5'-triphosphate form (AT-9010) by an α-thiophosphate renders it resistant to excision. The resulting α-thiotriphosphate, AT-9052, exists as two epimers (RP/SP). Through co-crystallization and activity assays, we show that the Sp isomer is preferentially used as a substrate by nucleotide diphosphate kinase (NDPK), and by SARS-CoV-2 nsp12, where its incorporation causes immediate chain-termination. The same -Sp isomer, once incorporated by nsp12, is also totally resistant to the excision by nsp10/nsp14 complex. However, unlike AT-9010, AT-9052-RP/SP no longer inhibits the N-terminal nucleotidylation domain of nsp12. We conclude that AT-9052-Sp exhibits a unique mechanism of action against SARS-CoV-2. Moreover, the thio modification provides a general approach to rescue existing NAs whose activity is hampered by coronavirus proofreading capacity.
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