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https://doi.org/10.3390/ph15020115
Title: | Discovery of Novel Andrographolide Derivatives as Antiviral Inhibitors against Human Enterovirus A71 | Authors: | Tan, Jie Kai Chen, Ran Lee, Regina Ching Hua Li, Feng Dai, Kun Zhou, Guo-Chun Chu, Justin Jang Hann |
Keywords: | Science & Technology Life Sciences & Biomedicine Chemistry, Medicinal Pharmacology & Pharmacy human enterovirus A71 andrographolide quinolinoxy olefin viral RNA replication host-targeting broad-spectrum anti-enterovirus agent MOUTH-DISEASE PANICULATA NEES HAND FOOT EPIDEMIC REPLICATION INFECTION TAIWAN SINGAPORE SULFONATE |
Issue Date: | 1-Feb-2022 | Publisher: | MDPI | Citation: | Tan, Jie Kai, Chen, Ran, Lee, Regina Ching Hua, Li, Feng, Dai, Kun, Zhou, Guo-Chun, Chu, Justin Jang Hann (2022-02-01). Discovery of Novel Andrographolide Derivatives as Antiviral Inhibitors against Human Enterovirus A71. PHARMACEUTICALS 15 (2). ScholarBank@NUS Repository. https://doi.org/10.3390/ph15020115 | Abstract: | 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. | Source Title: | PHARMACEUTICALS | URI: | https://scholarbank.nus.edu.sg/handle/10635/235427 | ISSN: | 1424-8247 | DOI: | 10.3390/ph15020115 |
Appears in Collections: | Staff Publications Elements |
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Discovery of Novel Andrographolide Derivatives as Antiviral Inhibitors against Human Enterovirus A71. .pdf | Published version | 4.94 MB | Adobe PDF | OPEN | Published | View/Download |
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