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TitleThe 2'-endo conformation of arabinose-CTP and arabinose-UTP inhibit viral polymerases by inducing long pauses.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateSep 5, 2025
AuthorsZiyang Xiao / Arnab Das / Abha Jain / Thomas K Anderson / Craig E Cameron / Jamie J Arnold / David Dulin / Robert N Kirchdoerfer /
PubMed AbstractKey to supporting human health in the face of evolving viruses is the development of novel antiviral drug scaffolds with the potential for broad inhibition of viral families. Nucleoside analogs are a ...Key to supporting human health in the face of evolving viruses is the development of novel antiviral drug scaffolds with the potential for broad inhibition of viral families. Nucleoside analogs are a key class of drugs that have demonstrated potential for the inhibition of several viral species. Here, we evaluate arabinose nucleotides (ara-NTP) as inhibitors of the SARS-CoV-2 and poliovirus polymerases using biochemistry, biophysics and structural biology. Ara-NTPs compete poorly with their natural counterparts for incorporation into RNA by viral polymerases. However, upon incorporation, ara-NMPs induce long polymerase pausing in both SARS-CoV-2 and poliovirus polymerase RNA elongation. Our studies suggest that subsequent nucleotide incorporation is inhibited at the catalytic step due to the 2'-endo sugar pucker of the incorporated ara-NMP.
External linksbioRxiv / PubMed:40909592 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.1 Å
Structure data

72038

9pyw

EMDB-72038, PDB-9pyw:
SARS-CoV-2 nsp7, nsp8 and nsp12 bound to a primer-template pair with incorporated ara-UMP
Method: EM (single particle) / Resolution: 3.1 Å

72053

9pyz

EMDB-72053, PDB-9pyz:
SARS-CoV-2 core polymerase complex bound to RNA, araUMP, and UTP
Method: EM (single particle) / Resolution: 3.1 Å

72054

9pz0

EMDB-72054, PDB-9pz0:
SARS-CoV-2 core polymerase complex with two UTP incorporation
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-UTP:
URIDINE 5'-TRIPHOSPHATE / UTP*YM

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
KeywordsVIRAL PROTEIN / RNA-dependent RNA polymerase (RdRp) / Viral RNA synthesis / arabinose UTP / nsp7 / nsp8 / nsp12 / Uridine triphosphate

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