A naturally occurring antiviral ribonucleotide encoded by the human genome

• Published in: Nature (London) Vol. 558; no. 7711; pp. 610 - 614
• Main Authors: Gizzi, Anthony S., Grove, Tyler L., Arnold, Jamie J., Jose, Joyce, Jangra, Rohit K., Garforth, Scott J., Du, Quan, Cahill, Sean M., Dulyaninova, Natalya G., Love, James D., Chandran, Kartik, Bresnick, Anne R., Cameron, Craig E., Almo, Steven C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2018; Nature Publishing Group
• Subjects: 13/109; 631/326/596/2553; 631/45/173; 631/45/49/1141; 639/638/45/320; 82/58; 82/80; 82/83; Animals; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral drugs; Biological response modifiers; Cells (Biology); Cellular immunity; Cellular proteins; Chlorocebus aethiops; Chromatography; CTP; Cytidine triphosphate; Cytidine Triphosphate - biosynthesis; Cytidine Triphosphate - chemistry; Cytidine Triphosphate - metabolism; Dengue fever; Dengue virus; Deoxyribonucleic acid; DNA; DNA viruses; Enzymes; Gene expression; Genome, Human - genetics; Genomes; Genomics; Glucose; HEK293 Cells; Hepatitis; Hepatitis C; Hepatitis C virus; Human genome; Humanities and Social Sciences; Humans; Immunologic research; Infection; Influenza; Influenza A; Interferon; Interferon-inducible protein; Kinases; Letter; Life cycles; Macrophages; Mammalian cells; Mammals; Mass spectrometry; Methionine; Molecular chains; multidisciplinary; Proteins; Proteins - genetics; Proteins - metabolism; Public health; Rabies; Replication; Resveratrol; Ribonucleic acid; Ribonucleotides; RNA; RNA polymerases; RNA viruses; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - metabolism; Science; Science (multidisciplinary); Scientific imaging; Substrate Specificity; Transcription Termination, Genetic; Vector-borne diseases; Vero Cells; Viral diseases; Viral infections; Virus diseases; Virus inactivation; Viruses; West Nile fever; West Nile virus; Zika virus; Zika Virus - enzymology; Zika Virus - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0238-4

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 strategies 1 . 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 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 . 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. Viperin inhibits the replication of various viruses by catalysing the conversion of CTP to ddhCTP, which is a unique nucleotide that functions as replication-chain terminator of RNA-dependent RNA polymerases.