A naturally occurring antiviral ribonucleotide encoded by the human genome

Viral infections continue to represent major public health challenges, demanding enhanced mechanistic understanding of the processes contributing to viral lifecycles for the realization of new therapeutic strategies(1). Viperin, a member of the radical S-adenosyl-L-methionine (SAM) superfamily of enzymes, is an interferon inducible protein implicated in inhibiting the replication of a remarkable range of RNA and DNA viruses, including dengue virus, West Nile virus, hepatitis C virus, influenza A virus, rabies virus(2) and HIV(3,4). Viperin has been suggested to elicit these broad antiviral activities through interactions with a large number of functionally unrelated host and viral proteins(3,4). In contrast, herein, we demonstrate that viperin catalyzes the conversion of cytidine triphosphate (CTP) to 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), a previously undescribed biologically relevant molecule, via a SAM-dependent radical mechanism. We show that mammalian cells expressing viperin, and macrophages stimulated with IFN-α, produce substantial quantities of ddhCTP. We also establish that ddhCTP acts as a chain terminator for the RNA-dependent RNA-polymerases from multiple members of the flavivirus family, and present evidence that ddhCTP directly inhibits in vivo replication of ZIKA virus. These findings suggest a partially unifying mechanism, based on intrinsic catalytic/enzymatic properties, for the broad antiviral effects of viperin, which involves the generation of a naturally occurring replication chain terminator encoded by mammalian genomes.