{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:43:54Z","timestamp":1792496634428,"version":"4.5.0"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"20","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM R35 153307"],"award-info":[{"award-number":["GM R35 153307"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM T32 132046"],"award-info":[{"award-number":["GM T32 132046"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2032-deoxy-3\u2032,4\u2032-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\u2032-deoxy-3\u2032-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.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00226","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:02:27Z","timestamp":1790834547000},"page":"3217-3225","source":"Crossref","is-referenced-by-count":0,"title":["Substrate Selectivity\nof Viperin Probed Using Anticancer-Related\nPyrimidine Nucleotide Analogs"],"prefix":"10.1021","volume":"65","author":[{"given":"Minshik","family":"Jo","sequence":"first","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Rivera-Santana","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8608-0687","authenticated-orcid":true,"given":"Hanyu","family":"Su","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dillon P.","family":"Langford","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1713-1683","authenticated-orcid":true,"given":"E. Neil G.","family":"Marsh","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2026102007161170500_cit1","doi-asserted-by":"publisher","first-page":"115741","DOI":"10.1016\/j.bcp.2023.115741","article-title":"Nucleoside-based anticancer drugs:\nMechanism of action and drug resistance","volume":"215","author":"Hruba","year":"2023","journal-title":"Biochem.\nPharmacol."},{"issue":"4","key":"2026102007161170500_cit2","doi-asserted-by":"publisher","first-page":"667","DOI":"10.3390\/v13040667","article-title":"Broad-Spectrum\nAntiviral Strategies\nand Nucleoside Analogues","volume":"13","author":"Geraghty","year":"2021","journal-title":"Viruses"},{"issue":"7","key":"2026102007161170500_cit3","doi-asserted-by":"publisher","first-page":"5792","DOI":"10.18632\/aging.102973","article-title":"Decitabine in combination\nwith low-dose cytarabine, aclarubicin and G-CSF tends to improve prognosis\nin elderly patients with high-risk AML","volume":"12","author":"Hong","year":"2020","journal-title":"Aging"},{"issue":"19","key":"2026102007161170500_cit4","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1056\/nejmoa2007764","article-title":"Remdesivir for the Treatment of Covid-19 \u2500 Final\nReport","volume":"383","author":"Beigel","year":"2020","journal-title":"New Engl. J. Med."},{"key":"2026102007161170500_cit5","doi-asserted-by":"publisher","DOI":"10.1590\/s1678-9946201961012","article-title":"Sofosbuvir, ribavirin and pegylated interferon for a daclatasvir-resistent\ngenotype 3 hepatitis C virus: case report and review","volume":"61","author":"Mucenic","year":"2019","journal-title":"Rev. Inst. Med. Trop. Sa\u0303o Paulo"},{"issue":"1","key":"2026102007161170500_cit6","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/ijc.23607","article-title":"Modes of action of the DNA methyltransferase\ninhibitors azacytidine\nand decitabine","volume":"123","author":"Stresemann","year":"2008","journal-title":"Int. J. Cancer"},{"issue":"6","key":"2026102007161170500_cit7","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.3892\/ijo.2014.2386","article-title":"Zebularine induces\nprolonged apoptosis effects via the caspase-3\/PARP\npathway in head and neck cancer cells","volume":"44","author":"Napso","year":"2014","journal-title":"Int.\nJ. Oncology"},{"issue":"3","key":"2026102007161170500_cit8","doi-asserted-by":"publisher","first-page":"910","DOI":"10.3892\/ijo.2012.1546","article-title":"Decitabine, a DNA\nmethyltransferase inhibitor, induces apoptosis in human leukemia cells\nthrough intracellular reactive oxygen species generation","volume":"41","author":"Shin","year":"2012","journal-title":"Int. J. Oncology"},{"issue":"18","key":"2026102007161170500_cit9","doi-asserted-by":"publisher","first-page":"2937","DOI":"10.1016\/0006-2952(82)90266-0","article-title":"Effect of ara-C\nincorporation on deoxyribonucleic acid synthesis in cells","volume":"31","author":"Major","year":"1982","journal-title":"Biochem. Pharmacol."},{"issue":"34","key":"2026102007161170500_cit10","doi-asserted-by":"publisher","first-page":"11873","DOI":"10.1021\/bi980959n","article-title":"Substrate\nconnectivity effects in the transition state\nfor cytidine deaminase","volume":"37","author":"Carlow","year":"1998","journal-title":"Biochemistry"},{"issue":"36","key":"2026102007161170500_cit11","doi-asserted-by":"publisher","first-page":"14324","DOI":"10.1073\/pnas.0706803104","article-title":"Enhanced\nsubunit interactions with\ngemcitabine-5\u2032-diphosphate inhibit ribonucleotide reductases","volume":"104","author":"Wang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102007161170500_cit12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.antiviral.2015.01.002","article-title":"Characterization\nof the activity of 2\u2032-C-methylcytidine against dengue virus\nreplication","volume":"116","author":"Lee","year":"2015","journal-title":"Antiviral Res."},{"issue":"1","key":"2026102007161170500_cit13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0163-7258(79)90023-8","article-title":"Antiviral\niodinated pyrimidine deoxyribonucleosides:\n5-iodo-2\u2032-deoxyuridine; 5\u2032-iodo-2\u2032-deoxycytidine;\n5-iodo-5\u2032-amino-2\u2032,5\u2032-didoxyuridine","volume":"7","author":"Prusoff","year":"1979","journal-title":"Pharmacol. Therapeut."},{"key":"2026102007161170500_cit14","doi-asserted-by":"publisher","first-page":"11513","DOI":"10.1074\/jbc.REV120.012784","article-title":"Viperin: an ancient\nradical SAM enzyme finds its place\nin modern cellular metabolism and innate immunity","volume":"295","author":"Ghosh","year":"2020","journal-title":"J. Biol. Chem."},{"key":"2026102007161170500_cit15","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1016\/j.jmb.2013.10.019","article-title":"The role of viperin in the innate antiviral response","volume":"426","author":"Helbig","year":"2014","journal-title":"J. Mol. Biol."},{"issue":"4","key":"2026102007161170500_cit16","doi-asserted-by":"publisher","first-page":"15125","DOI":"10.1073\/pnas.011593298","article-title":"Viperin (cig5), an IFN-inducible antiviral protein\ndirectly induced by human cytomegalovirus Proc","volume":"98","author":"Chin","year":"2001","journal-title":"Natl. Acad. Sci. U.S.A."},{"issue":"52","key":"2026102007161170500_cit17","doi-asserted-by":"publisher","first-page":"26806","DOI":"10.1074\/jbc.M116.751040","article-title":"Does Viperin\nFunction as a Radical S-Adenosyl-l-methionine-dependent\nEnzyme in Regulating Farnesylpyrophosphate Synthase Expression and\nActivity?","volume":"291","author":"Makins","year":"2016","journal-title":"J. Biol. Chem."},{"issue":"5","key":"2026102007161170500_cit18","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1021\/acs.biochem.9b00741","article-title":"Structural Basis\nof the Substrate Selectivity of Viperin","volume":"59","author":"Fenwick","year":"2020","journal-title":"Biochemistry"},{"issue":"7840","key":"2026102007161170500_cit19","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41586-020-2762-2","article-title":"Prokaryotic viperins produce diverse antiviral molecules","volume":"589","author":"Bernheim","year":"2021","journal-title":"Nature"},{"issue":"7711","key":"2026102007161170500_cit20","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/s41586-018-0238-4","article-title":"A naturally occurring antiviral ribonucleotide\nencoded\nby the human genome","volume":"558","author":"Gizzi","year":"2018","journal-title":"Nature"},{"key":"2026102007161170500_cit21","doi-asserted-by":"publisher","first-page":"2751","DOI":"10.3389\/fimmu.2019.02751","article-title":"Interferon-Independent\nInnate Responses to Cytomegalovirus","volume":"10","author":"Ashley","year":"2019","journal-title":"Front.\nImmunol."},{"issue":"1","key":"2026102007161170500_cit22","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1099\/vir.0.033860-0","article-title":"Viperin inhibits\nhepatitis C virus replication by interfering with\nbinding of NS5A to host protein hVAP-33","volume":"93","author":"Wang","year":"2012","journal-title":"J.\nGen. Virol."},{"issue":"12","key":"2026102007161170500_cit23","doi-asserted-by":"publisher","first-page":"4447","DOI":"10.1172\/JCI63120","article-title":"Viperin restricts chikungunya virus replication and\npathology","volume":"122","author":"Teng","year":"2012","journal-title":"J. Clin. Invest."},{"issue":"4","key":"2026102007161170500_cit24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002178","article-title":"Viperin is induced\nfollowing dengue virus type-2 (DENV-2)\ninfection and has anti-viral actions requiring the C-terminal end\nof viperin","volume":"7","author":"Helbig","year":"2013","journal-title":"PLoS Negl. Trop. Dis."},{"issue":"22","key":"2026102007161170500_cit25","doi-asserted-by":"publisher","first-page":"11557","DOI":"10.1128\/JVI.05519-11","article-title":"The Interferon-Inducible\nGene viperin Restricts West\nNile Virus Pathogenesis","volume":"85","author":"Szretter","year":"2011","journal-title":"J. Virol."},{"key":"2026102007161170500_cit26","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1007\/s10753-024-02076-5","article-title":"Crucial\nRoles of RSAD2\/viperin in Immunomodulation, Mitochondrial Metabolism\nand Autoimmune Diseases","volume":"48","author":"Chen","year":"2025","journal-title":"Inflammation"},{"issue":"24","key":"2026102007161170500_cit27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI165907","article-title":"The rise\nof viperin: the emerging\nrole of viperin in cancer progression","volume":"132","author":"Weinstein","year":"2022","journal-title":"J. Clin.\nInvest."},{"issue":"17","key":"2026102007161170500_cit28","doi-asserted-by":"publisher","first-page":"6888","DOI":"10.1074\/jbc.RA119.007719","article-title":"Viperin interacts with the kinase\nIRAK1 and the E3 ubiquitin ligase TRAF6, coupling innate immune signaling\nto antiviral ribonucleotide synthesis","volume":"294","author":"Dumbrepatil","year":"2019","journal-title":"J. Biol.\nChem."},{"issue":"6033","key":"2026102007161170500_cit29","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1126\/science.1202007","article-title":"Human Cytomegalovirus\nDirectly Induces the Antiviral Protein Viperin to Enhance Infectivity","volume":"332","author":"Seo","year":"2011","journal-title":"Science"},{"issue":"24","key":"2026102007161170500_cit30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI157302","article-title":"The interferon-inducible\nprotein viperin controls cancer metabolic\nreprogramming to enhance cancer progression","volume":"132","author":"Choi","year":"2022","journal-title":"J. Clin. Invest."},{"issue":"4","key":"2026102007161170500_cit31","doi-asserted-by":"publisher","first-page":"108359","DOI":"10.1016\/j.jbc.2025.108359","article-title":"Viperin expression\nleads to downregulation of mitochondrial\ngenes through misincorporation of ddhCTP by mitochondrial RNA polymerase","volume":"301","author":"Majhi","year":"2025","journal-title":"J. Biol. Chem."},{"key":"2026102007161170500_cit32","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1021\/acs.biochem.9b01090","article-title":"Interactions\nbetween Viperin, Vesicle-Associated Membrane Protein A, and Hepatitis\nC Virus Protein NS5A Modulate Viperin Activity and NS5A Degradation","volume":"59","author":"Ghosh","year":"2020","journal-title":"Biochemistry"},{"key":"2026102007161170500_cit33","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1021\/acsbiomedchemau.3c00014","article-title":"Chemoenzymatic Synthesis of 3\u2032-Deoxy-3\u2032,4\u2032-didehydro-cytidine\ntriphosphate (ddhCTP)","volume":"3","author":"Lee","year":"2023","journal-title":"ACS Bio Med Chem Au"},{"key":"2026102007161170500_cit34","doi-asserted-by":"publisher","first-page":"4755","DOI":"10.1021\/ja01484a016","article-title":"Thiation of Nucleosides.\nIV. The Synthesis of 5-Fluoro-2\u2019-deoxycytidine and Related\nCompounds1,2","volume":"83","author":"Wempen","year":"1961","journal-title":"J. Am. Chem. Soc."},{"key":"2026102007161170500_cit35","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1053\/j.seminhematol.2005.05.002","article-title":"Pharmacology\nof 5-Aza-2\u2032-deoxycytidine (decitabine)","volume":"42","author":"Momparler","year":"2005","journal-title":"Semin. Hematol."},{"key":"2026102007161170500_cit36","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0:\nNew Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Info. Model."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.6c00226","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/65\/20\/3217\/68722089\/acs.biochem.6c00226.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/65\/20\/3217\/68722089\/acs.biochem.6c00226.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:29:11Z","timestamp":1792495751000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/65\/20\/3217\/5443129\/Substrate-Selectivity-of-Viperin-Probed-Using"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":36,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2026,10,1]]},"published-print":{"date-parts":[[2026,10,20]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.6c00226","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}