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Discovery of 14S-(2'-chloro-4'-nitrophenoxy)-8R/S,17-epoxy andrographolide as EV-A71 infection inhibitor.

Abstract
Human enterovirus A71 (EV-A71) is a major etiological agent of hand-foot-and-mouth disease (HFMD) and there is presently no internationally approved antiviral against EV-A71. In this study, it is disclosed that 14S-(2'-chloro-4'-nitrophenoxy)-8R/S,17-epoxy andrographolide (2) was discovered to be an effective inhibitor against EV-A71 infection showing significant reduction of viral titre. In addition to EV-A71, compound 2 exerts broad-spectrum antiviral effects against other enteroviruses. It is revealed that compound 2 inhibits the post-entry stages of EV-A71 viral replication cycle and significantly reduces viral protein expression of structural proteins such as VP0 and VP2 via inhibiting EV-A71 RNA replication. Moreover, the inhibitory property of compound 2 is specific to viral RNA replication. Furthermore, compound 2 is more likely to target a host factor in EV-A71 RNA replication. As a result, introduction of epoxide at positions 8 and 17 of andrographolide is effective for anti-EV-A71 infection and is a potential anti-EV-A71 strategy. Further work to discover more potent andrographolide derivatives and elucidate comprehensive SAR is under way.
AuthorsKun Dai, Jie Kai Tan, Weiyi Qian, Regina Ching Hua Lee, Justin Jang Hann Chu, Guo-Chun Zhou
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 194 Pg. 114820 (12 2021) ISSN: 1873-2968 [Electronic] England
PMID34748818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Elsevier Inc. All rights reserved.
Chemical References
  • Diterpenes
  • andrographolide
Topics
  • Animals
  • Cell Survival (drug effects, physiology)
  • Chlorocebus aethiops
  • Diterpenes (chemistry, pharmacology, therapeutic use)
  • Dose-Response Relationship, Drug
  • Drug Discovery (methods)
  • Enterovirus A, Human (drug effects, physiology)
  • Enterovirus Infections (drug therapy, metabolism)
  • Humans
  • Vero Cells
  • Virus Replication (drug effects, physiology)

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