2. Academic Validation
  3. Effects of the oxoaporphine alkaloid hernandonine on dengue virus. Evidence for its mechanisms of action

Effects of the oxoaporphine alkaloid hernandonine on dengue virus. Evidence for its mechanisms of action

  • Phytomedicine. 2024 Nov:134:155986. doi: 10.1016/j.phymed.2024.155986.
Ying-Chieh Liao 1,  Chih-Ching Yeh 2,  Yu-Fan Chueh 3,  Mei-Shu Huang 4,  Jhong-Syuan Wu 1,  Ying-Xu Wen 1,  Yu-Tzu Chang 1,  Yi-Ru Lai 1,  Jih-Jung Chen 5,  Tsung-Hsien Chang 6
Affiliations

Affiliations

  • 1 Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei 114, Taiwan.
  • 2 Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung 821, Taiwan.
  • 3 Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei 114, Taiwan; Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica; and Graduate Institute of Life Sciences, National defense Medical Center, Taipei 114, Taiwan.
  • 4 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
  • 5 Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan. Electronic address: chenjj@ym.edu.tw.
  • 6 Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei 114, Taiwan. Electronic address: changth@mail.ndmctsgh.edu.tw.
PMID: 39232285 DOI: 10.1016/j.phymed.2024.155986
Abstract

Background: Dengue, caused by the Dengue virus (Orthoflavivirus dengue, encompassing DENV types 1-4), is a member of the Flaviviridae family. The symptoms of dengue range from subclinical or mild manifestations to potentially fatal complications. The management of severe dengue is exceptionally challenging due to the absence of effective Antiviral medications. In this context, Natural Products, whether in the form of pure compounds or standardized plant extracts, have emerged as a promising source for the development of novel Antiviral therapeutics. Hernandonine, an oxoaporphine alkaloid found in Hernandia nymphaeifolia (C. Presl) Kubitzki. serves both as a metabolite and an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase.

Purpose: This study investigated the ability of hernandonine to inhibit DENV Infection and explored its potential mechanisms.

Study design: To assess the in vitro anti-DENV activity, cells or induced pluripotent stem cell (iPSC)-derived cerebral organoids were exposed to hernandonine before or after Infection with DENV. Along with hernandonine, the endocytosis modulators, genistein, wortmannin, Methyl-β-cyclodextrin (MβCD) and lovastatin, were used in the assays.

Methods: The DENV infectivity and virion production in cells or cerebral organoids treated with compounds were determined. Various methods, including cell and cerebral organoids imaging, protein and gene detection were conducted to explore their Antiviral mechanisms.

Results: The results revealed notable Antiviral properties of hernandonine, particularly in inhibiting DENV during the early stages of Infection. Mechanistic analysis demonstrated that, akin to genistein, wortmannin, methyl-β-cyclodextrin (MβCD), and lovastatin, hernandonine exerted an influence on cholesterol-rich lipid rafts. It also restrained the pseudopodial movement ability of cells, potentially through the downregulation of Cytoskeleton and endocytosis regulatory genes or protein expression. Moreover, hernandonine's virucidal activity was demonstrated. Hernandonine's inhibition of DENV Infection was further validated in a disease-relevant iPSC-derived cerebral organoids model, a novel DENV-2 Infection system worthy of further application.

Conclusion: This study evidenced the potential of hernandonine as a novel candidate in the fight against DENV Infection.

Keywords

Dengue virus; Hernandonine; Lipid rafts; Pseudopodia.

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