Viral infections continue to represent major challenges to public health, and an enhanced mechanistic understanding of the processes that contribute to viral life cycles is necessary for the development of new therapeutic strategies1. Viperin, a member of the radical S-adenosyl-l-methionine (SAM) superfamily of enzymes, is an interferon-inducible protein implicated in the inhibition of replication of a broad range of RNA and DNA viruses, including dengue virus, West Nile virus, hepatitis C virus, influenza A virus, rabies virus2 and HIV3,4. Viperin has been suggested to elicit these broad antiviral activities through interactions with a large number of functionally unrelated host and viral proteins3,4. Here we demonstrate that viperin catalyses the conversion of cytidine triphosphate (CTP) to 3ʹ-deoxy-3′,4ʹ-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 IFNα 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 genus, and show that ddhCTP directly inhibits replication of Zika virus in vivo. These findings suggest a partially unifying mechanism for the broad antiviral effects of viperin that is based on the intrinsic enzymatic properties of the protein and involves the generation of a naturally occurring replication-chain terminator encoded by mammalian genomes.
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We thank S. J. Booker for helpful discussions, L. Nordstroem (Chemical Synthesis & Biology Core Facility) for synthesis of ddhC and R. Sharma and J. Perryman for assistance with construction of RdRp expression plasmids and purification of RdRp enzymes. This work was supported by National Institutes of Health (NIH) Grants R21-AI133329 (T.L.G. and S.C.A.), P01-GM118303-01 (J. A. Gerlt and S.C.A.), U54-GM093342 (J. A. Gerlt and S.C.A.), U54-GM094662 (S.C.A.), R01-AI045818 (C.E.C.), Pennsylvania State University Start-Up Funds (J.J.), and the Price Family Foundation (S.C.A.). We acknowledge the Albert Einstein Anaerobic Structural and Functional Genomics Resource (http://www.nysgxrc.org/psi3/anaerobic.html).
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Mammalian Genome (2018)