{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:59:38Z","timestamp":1792159178341,"version":"4.4.0"},"reference-count":167,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI158775"],"award-info":[{"award-number":["R01AI158775"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI179926"],"award-info":[{"award-number":["R01AI179926"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Picornaviruses cause substantial human and veterinary disease, yet direct-acting antivirals remain limited. The nonstructural protein 2C is among the most conserved picornaviral proteins and has ATPase and helicase-like activities. 2C is involved in membrane remodeling, RNA replication, encapsidation, morphogenesis, and multiple virus\u2013host interactions. In this review, we summarize the domain architecture and structural biology of 2C, highlighting the N-terminal membrane-binding region, the ATPase core, the C-terminal helical domain, and accessory motifs that regulate oligomerization and ligand recognition. We further review experimentally supported roles of 2C throughout the viral replication cycle and compare known inhibitors, resistance mutations, and emerging design strategies. Collectively, current evidence supports 2C as a tractable yet still underexploited antiviral target for medically important picornaviruses.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00387","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:45:06Z","timestamp":1785149106000},"page":"2505-2528","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Picornavirus\nNonstructural 2C Protein: Structure,\nFunction, and Antiviral Discovery"],"prefix":"10.1021","volume":"12","author":[{"given":"Kan","family":"Li","sequence":"first","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjin","family":"Fan","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4845-4621","authenticated-orcid":true,"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08552"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"2026081410081654700_cit1","doi-asserted-by":"crossref","DOI":"10.1128\/9781555816698","volume-title":"The Picornaviruses","author":"Ehrenfeld","year":"2010"},{"issue":"3","key":"2026081410081654700_cit2","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.antiviral.2010.12.007","article-title":"Picornavirus non-structural proteins as targets for\nnew anti-virals with broad activity","volume":"89","author":"Norder","year":"2011","journal-title":"Antiviral\nRes."},{"issue":"10","key":"2026081410081654700_cit3","doi-asserted-by":"publisher","first-page":"2421","DOI":"10.1099\/jgv.0.000911","article-title":"ICTV\nVirus Taxonomy Profile: Picornaviridae","volume":"98","author":"Zell","year":"2017","journal-title":"J. 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Biomed. Sci."},{"issue":"10","key":"2026081410081654700_cit33","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202200541","article-title":"Development of Enterovirus Antiviral Agents That Target\nthe Viral 2C Protein","volume":"18","author":"Kejriwal","year":"2023","journal-title":"ChemMedChem"},{"key":"2026081410081654700_cit34","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2024.1347615","article-title":"Picornavirus 2C proteins: structure-function\nrelationships and interactions\nwith host factors","volume":"14","author":"Yin","year":"2024","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"4","key":"2026081410081654700_cit35","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1602573","article-title":"Crystal structure of\n2C helicase from enterovirus 71","volume":"3","author":"Guan","year":"2017","journal-title":"Sci. Adv."},{"issue":"9","key":"2026081410081654700_cit36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007304","article-title":"Crystal structure\nof a soluble fragment of poliovirus 2CATPase","volume":"14","author":"Guan","year":"2018","journal-title":"PLoS Pathog."},{"issue":"1","key":"2026081410081654700_cit37","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj7615","article-title":"Fluoxetine targets\nan allosteric site in the enterovirus 2C AAA+ ATPase and stabilizes\na ring-shaped hexameric complex","volume":"8","author":"Hurdiss","year":"2022","journal-title":"Sci. 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Chem."},{"issue":"13","key":"2026081410081654700_cit40","doi-asserted-by":"publisher","first-page":"14041","DOI":"10.1021\/acs.jmedchem.5c01219","article-title":"Design of\na Fluorescence Polarization\nProbe for Enterovirus 2C Proteins","volume":"68","author":"Li","year":"2025","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026081410081654700_cit41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61083-8","article-title":"A rationally designed\n2C inhibitor prevents enterovirus D68-infected\nmice from developing paralysis","volume":"16","author":"Li","year":"2025","journal-title":"Nat. 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Chem."},{"issue":"2","key":"2026081410081654700_cit45","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.virol.2005.08.044","article-title":"Testing the\nmodularity of the N-terminal amphipathic\nhelix conserved in picornavirus 2C proteins and hepatitis C NS5A protein","volume":"344","author":"Teterina","year":"2006","journal-title":"Virology"},{"issue":"2","key":"2026081410081654700_cit46","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/S0168-1702(98)00016-1","article-title":"Amino-terminal region\nof poliovirus\n2C protein is sufficient for membrane binding","volume":"54","author":"Echeverri","year":"1998","journal-title":"Virus Res."},{"issue":"12","key":"2026081410081654700_cit47","doi-asserted-by":"publisher","first-page":"8962","DOI":"10.1128\/jvi.71.12.8962-8972.1997","article-title":"Poliovirus\n2C protein determinants of membrane binding and rearrangements in\nmammalian cells","volume":"71","author":"Teterina","year":"1997","journal-title":"J. Virol."},{"issue":"1","key":"2026081410081654700_cit48","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1006\/viro.1994.1329","article-title":"Membrane rearrangement\nand vesicle induction by recombinant poliovirus 2C and 2BC in human\ncells","volume":"202","author":"Cho","year":"1994","journal-title":"Virology"},{"issue":"12","key":"2026081410081654700_cit49","doi-asserted-by":"publisher","DOI":"10.3390\/v12121466","article-title":"An Amphipathic Alpha-Helix\nDomain from Poliovirus 2C Protein Tubulate Lipid Vesicles","volume":"12","author":"Varkey","year":"2020","journal-title":"Viruses"},{"issue":"2","key":"2026081410081654700_cit50","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.cell.2019.05.030","article-title":"Viral Generated Inter-Organelle Contacts\nRedirect Lipid Flux for Genome Replication","volume":"178","author":"Laufman","year":"2019","journal-title":"Cell"},{"issue":"33","key":"2026081410081654700_cit51","doi-asserted-by":"publisher","first-page":"22012","DOI":"10.1074\/jbc.M109.031807","article-title":"Poliovirus\n2C protein forms homo-oligomeric structures required for ATPase activity","volume":"284","author":"Adams","year":"2009","journal-title":"J. Biol. Chem."},{"issue":"Pt 10","key":"2026081410081654700_cit52","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1107\/s090744491002809x","article-title":"The 2C putative helicase\nof echovirus 30 adopts a hexameric\nring-shaped structure","volume":"66","author":"Papageorgiou","year":"2010","journal-title":"Acta Crystallogr., Sect.\nD: Biol. Crystallogr."},{"issue":"5","key":"2026081410081654700_cit53","doi-asserted-by":"publisher","first-page":"2627","DOI":"10.1128\/AAC.02182-15","article-title":"Screening\nof a Library of FDA-Approved Drugs Identifies Several Enterovirus\nReplication Inhibitors That Target Viral Protein 2C","volume":"60","author":"Ulferts","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081410081654700_cit54","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.103981","article-title":"Development of broad-spectrum\nenterovirus antivirals based on quinoline scaffold","volume":"101","author":"Musharrafieh","year":"2020","journal-title":"Bioorg. Chem."},{"issue":"Pt 6","key":"2026081410081654700_cit55","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1099\/vir.0.062497-0","article-title":"A C-terminal,\ncysteine-rich site in poliovirus 2C(ATPase) is required for morphogenesis","volume":"95","author":"Wang","year":"2014","journal-title":"J. Gen. Virol."},{"issue":"7","key":"2026081410081654700_cit56","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005067","article-title":"Human Enterovirus Nonstructural\nProtein 2CATPase Functions as Both an RNA Helicase and ATP-Independent\nRNA Chaperone","volume":"11","author":"Xia","year":"2015","journal-title":"PLoS Pathog."},{"issue":"11","key":"2026081410081654700_cit57","doi-asserted-by":"publisher","first-page":"8105","DOI":"10.1016\/S0021-9258(18)53068-4","article-title":"Poliovirus protein\n2C has ATPase and GTPase activities","volume":"268","author":"Rodri\u0301guez","year":"1993","journal-title":"J. Biol.\nChem."},{"issue":"11","key":"2026081410081654700_cit58","doi-asserted-by":"publisher","first-page":"6992","DOI":"10.1074\/jbc.274.11.6992","article-title":"Characterization of the nucleoside\ntriphosphatase activity\nof poliovirus protein 2C reveals a mechanism by which guanidine inhibits\npoliovirus replication","volume":"274","author":"Pfister","year":"1999","journal-title":"J. Biol. Chem."},{"issue":"7100","key":"2026081410081654700_cit59","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nature04943","article-title":"Mechanism of DNA translocation in a replicative hexameric\nhelicase","volume":"442","author":"Enemark","year":"2006","journal-title":"Nature"},{"issue":"9","key":"2026081410081654700_cit60","doi-asserted-by":"publisher","first-page":"5205","DOI":"10.1128\/JVI.00245-13","article-title":"The nonstructural\nprotein 2C of a Picorna-like virus displays nucleic acid helix destabilizing\nactivity that can be functionally separated from its ATPase activity","volume":"87","author":"Cheng","year":"2013","journal-title":"J. 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