Incorporation of arabinose-CTP and arabinose-UTP inhibits viral polymerases by inducing long pauses

TL;DR

This study explores how arabinose nucleotides can inhibit viral polymerases by causing long pauses during RNA synthesis, potentially leading to new antiviral treatments.

Contribution

The novel finding is that arabinose nucleotides induce long pauses in viral polymerases after incorporation, inhibiting further RNA synthesis.

Findings

Ara-NTPs poorly compete with natural nucleotides for incorporation into RNA by viral polymerases.

Incorporation of ara-NMPs causes long pauses during RNA elongation by SARS-CoV-2 and poliovirus polymerases.

Ara-NMP incorporation inhibits further nucleotide addition at the catalytic step of RNA synthesis.

Abstract

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 severe acute respiratory syndrome coronavirus 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 during both severe acute respiratory syndrome coronavirus 2 and poliovirus polymerase RNA elongation. Our studies suggest that following ara-NMP incorporation, additional nucleotide incorporation is inhibited at the catalytic step.

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