{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T01:09:59Z","timestamp":1776906599591,"version":"3.51.2"},"reference-count":71,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["30973621"],"award-info":[{"award-number":["30973621"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U0632001"],"award-info":[{"award-number":["U0632001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001459","name":"Ministry of Education","doi-asserted-by":"publisher","award":["MOE2017-T2-2-014"],"award-info":[{"award-number":["MOE2017-T2-2-014"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NRF Competitive Research Programme","award":["NRF-CRP21-2018-0004"],"award-info":[{"award-number":["NRF-CRP21-2018-0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Hand-foot-and-mouth disease (HFMD) caused by human enterovirus A71 (EV-A71) infection has been associated with severe neurological complications. With the lack of an internationally approved antiviral, coupled with a surge in outbreaks globally, EV-A71 has emerged as a neurotropic virus of high clinical importance. Andrographolide has many pharmacological effects including antiviral activity and its derivative, andrographolide sulfonate, has been used in China clinically to treat EV-A71 infections. This study sought to identify novel andrographolide derivatives as EV-A71 inhibitors and elucidate their antiviral mode of action. Using an immunofluorescence-based phenotypic screen, we identified novel EV-A71 inhibitors from a 344-compound library of andrographolide derivatives and validated them with viral plaque assays. Among these hits, ZAF-47, a quinolinoxy-andrographolide, was selected for downstream mechanistic studies. It was found that ZAF-47 acts on EV-A71 post-entry stages and inhibits EV-A71 protein expression. Subsequent luciferase studies confirm that ZAF-47 targets EV-A71 genome RNA replication specifically. Unsuccessful attempts in generating resistant mutants led us to believe a host factor is likely to be involved which coincide with the finding that ZAF-47 exhibits broad-spectrum antiviral activity against other enteroviruses (CV-A16, CV-A6, Echo7, CV-B5, CV-A24 and EV-D68). Furthermore, ZAF-46 and ZAF-47, hits from the screen, were derivatives of the same series containing quinolinoxy and olefin modifications, suggesting that an andrographolide scaffold mounted with these unique moieties could be a potential anti-EV-A71\/HFMD strategy.<\/jats:p>","DOI":"10.3390\/ph15020115","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T22:46:32Z","timestamp":1642545992000},"page":"115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Discovery of Novel Andrographolide Derivatives as Antiviral Inhibitors against Human Enterovirus A71"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0095-9591","authenticated-orcid":false,"given":"Jie Kai","family":"Tan","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 117545, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ran","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 117545, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3145-223X","authenticated-orcid":false,"given":"Guo-Chun","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 117545, Singapore"},{"name":"Infectious Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore"},{"name":"Collaborative and Translation Unit for HFMD, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/chromsci\/bmaa091","article-title":"Andrographolide: A Review of Analytical Methods","volume":"59","author":"Patil","year":"2021","journal-title":"J. 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