Substrate Selectivity of Viperin Probed Using Anticancer-Related Pyrimidine Nucleotide Analogs.

Authors

Minshik Jo, Victor Rivera-Santana, Hanyu Su, Dillon P Langford, E Neil G Marsh

Published in

Biochemistry. Volume 65. Issue 20. Pages 3217-3225. Oct 20, 2026.

Abstract

Many antiviral and anticancer drugs are based on the structure of pyrimidine nucleosides. Once phosphorylated, they function by interfering with either DNA or RNA replication or transcription. The antiviral enzyme, viperin, catalyzes the dehydration of CTP to produce 3'-deoxy-3',4'-didehydroCTP (ddhCTP), which functions as a natural antiviral nucleotide. Various drugs mimic the structure of CTP, and furthermore, viperin is upregulated in some cancers and autoimmune diseases. Therefore, we examined whether such drugs may be substrates for viperin. A panel of eight commercially available nucleosides, including several clinically used drugs, were enzymatically converted to their triphosphate forms and investigated as substrates for viperin. Five of the nucleotides were not substrates, indicating that viperin has generally high specificity for CTP. Two nucleotides, 3'-deoxy-3'-fluoroCTP and cytarabine triphosphate elicited reductive cleavage of SAM and were converted to their dehydrated products by viperin. The last compound, gemcitabine triphosphate, elicited reductive cleavage of SAM, but no dehydrated product was observed, implying that it activates SAM cleavage without undergoing hydrogen atom abstraction. The implications of these results are discussed.

PMID:
42899591
Bibliographic data and abstract were imported from PubMed on 21 Oct 2026.

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