{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:25:22Z","timestamp":1791433522928,"version":"4.3.3"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T00:00:00Z","timestamp":1738972800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The lack of effective antiviral treatments for enteroviruses, including human enterovirus A71 (EV\u2010A71), have resulted in an immense global healthcare burden associated with hand\u2010foot\u2010and\u2010mouth disease (HFMD). Rocaglates and aglains belong to a family of compounds produced by <jats:italic>Aglaia<\/jats:italic> genus plants. Since the initial discovery of rocaglates in 1982, various rocaglates and aglains have been synthesized and extensively studied mainly as anticancer agents. Here, we report the discovery of a novel aglain derivative as a potential EV\u2010A71 inhibitor. From an immunofluorescence\u2010based phenotypic screen of a library of 296 rocaglate and aglain derivatives, we identified a lead aglain which effectively suppressed EV\u2010A71 replication by 2.3\u2009log fold at a non\u2010cytotoxic concentration, with a host cell CC<jats:sub>50<\/jats:sub> of 21.78\u2009\u00b5M, an EV\u2010A71 infection EC<jats:sub>50<\/jats:sub> of 3.57\u2009\u00b5M, and a selectivity index of 6.1. Further validation revealed inhibition of EV\u2010A71 across multiple human cell types and a pan\u2010enterovirus inhibitory spectrum against other enteroviruses. Subsequent mechanistic investigation revealed interference with EV\u2010A71 intracellular post\u2010entry events including viral RNA transcription and translation. Findings from this study have established a strong foundation for development of aglain scaffolds as much needed antiviral agents for HFMD, paving the way for future medicinal chemistry optimization and <jats:italic>in vivo<\/jats:italic> studies.<\/jats:p>","DOI":"10.1002\/jmv.70228","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:25:50Z","timestamp":1739251550000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>In Vitro<\/i> Discovery of a Therapeutic Lead for HFMD From a Library Screen of Rocaglates\/Aglains"],"prefix":"10.1002","volume":"97","author":[{"given":"Adrian","family":"Oo","sequence":"first","affiliation":[{"name":"Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5667-4894","authenticated-orcid":false,"given":"Angel","family":"Borge","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Center for Molecular Discovery (BU\u2010CMD) Boston University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina Ching Hua","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrill Kafi","family":"Salim","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Center for Molecular Discovery (BU\u2010CMD) Boston University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8531-3863","authenticated-orcid":false,"given":"Michael","family":"Ricca","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Center for Molecular Discovery (BU\u2010CMD) Boston University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah Yuhui","family":"Fong","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Alonso","sequence":"additional","affiliation":[{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Immunology Programme, Life Sciences Institute National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-484X","authenticated-orcid":false,"given":"Lauren E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Center for Molecular Discovery (BU\u2010CMD) Boston University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2991-5680","authenticated-orcid":false,"suffix":"Jr.","given":"John A.","family":"Porco","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Center for Molecular Discovery (BU\u2010CMD) Boston University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-6819","authenticated-orcid":false,"given":"Justin Jang Hann","family":"Chu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"},{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) Singapore Singapore"},{"name":"NUSMed Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-023-00908-4"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.08.017"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-022-07661-3"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2018.04.007"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-019-4153-6"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1721159115"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2024.02.026"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-1401-9562"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-35765-6"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2022.102158"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006778"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm201263k"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2021.105012"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9030540"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2024.105976"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01357"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-7091-0748-5_1"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja511728b"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2006.09.084"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/np000341q"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/np3007588"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2007.05.074"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2007.06.016"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201707539"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja305342f"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201602953"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15020115"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2017.04.008"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560071008"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja002627n"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci9002393"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065948"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-020-0615-9"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10616-010-9313-x"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28915"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/v11050467"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02106-06"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.304"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh-2017-000442"},{"key":"e_1_2_9_42_1","unstructured":"CDC. Non\u2010Polio Enterovirus Outbreaks. June 4 2024 accessed July 3 2024 https:\/\/www.cdc.gov\/non-polio-enterovirus\/outbreak-surveillance."},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15010075"},{"key":"e_1_2_9_44_1","first-page":"ofz284","volume-title":"Economic Burden Attributed to Children Presenting to Hospitals With hand, Foot, and Mouth Disease in Vietnam","author":"Nhan L. N. T.","year":"2019"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268815001569"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v17.i36.4135"}],"container-title":["Journal of Medical Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.70228","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T07:21:18Z","timestamp":1744442478000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmv.70228"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1002\/jmv.70228"],"URL":"https:\/\/doi.org\/10.1002\/jmv.70228","archive":["Portico"],"relation":{},"ISSN":["0146-6615","1096-9071"],"issn-type":[{"value":"0146-6615","type":"print"},{"value":"1096-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70228"}}