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Background <p>Dengue virus (DENV) infects millions of individuals annually, yet no specific antiviral therapy exists. Autophagy, a conserved cellular degradation pathway, is activated during DENV infection and supports the production of infectious virions. Although autophagy modulation has emerged as a potential antiviral strategy, few small-molecule autophagy inhibitors with both potent anti-dengue activity and low cytotoxicity have been reported. Thus, identifying novel, safe, and effective autophagy-targeting compounds remains an important unmet need for host-directed antiviral development.</p> Methods <p>We performed a high-content imaging screen of a natural product-derived compound library to identify autophagy inhibitors. Candidate compounds were evaluated for autophagy inhibition and anti-dengue activity using LC3 puncta quantification and plaque assays. The most potent compound was further characterized by immunoblotting to assess autophagy inhibition. Its effects on DENV genome replication, viral protein expression, and infectious particle production were examined by qRT-PCR, immunofluorescence imaging, flow cytometry, and plaque assays. Cytotoxicity was assessed using the MTS assay.</p> Results <p>The screen identified HM-013, a 1,4-naphthoquinone derivative structurally related to lawsone, lapachol, juglone, and plumbagin, as a potent autophagy inhibitor. HM-013 reduced autophagosome formation in a dose-dependent manner at low micromolar concentrations and significantly suppressed DENV infectious particle production. Mechanistically, HM-013 did not inhibit viral genome replication but instead blocked a late stage of the viral life cycle. The compound demonstrated low cytotoxicity in human liver and monocytic cells.</p> Conclusions <p>HM-013 is a promising autophagy inhibitor with potent anti-DENV activity and low cytotoxicity, supporting its further development as a potential dengue therapeutic.</p>

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A novel potent autophagy inhibitor HM-013 limits production of infectious dengue virus particles

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Jitra Limthongkul,
  • Sineenart Attanonchai,
  • Tanpitcha Yodweerapong,
  • Orakot Simanurak,
  • Alisa Tubsuwan,
  • Phongthon Kanjanasirirat,
  • Tanawadee Khumpanied,
  • Supawan Jamnongsong,
  • Somponnat Sampattavanich,
  • Sukathida Ubol,
  • Suparerk Borwornpinyo,
  • Poonsakdi Ploypradith,
  • Marisa Ponpuak

摘要

Background

Dengue virus (DENV) infects millions of individuals annually, yet no specific antiviral therapy exists. Autophagy, a conserved cellular degradation pathway, is activated during DENV infection and supports the production of infectious virions. Although autophagy modulation has emerged as a potential antiviral strategy, few small-molecule autophagy inhibitors with both potent anti-dengue activity and low cytotoxicity have been reported. Thus, identifying novel, safe, and effective autophagy-targeting compounds remains an important unmet need for host-directed antiviral development.

Methods

We performed a high-content imaging screen of a natural product-derived compound library to identify autophagy inhibitors. Candidate compounds were evaluated for autophagy inhibition and anti-dengue activity using LC3 puncta quantification and plaque assays. The most potent compound was further characterized by immunoblotting to assess autophagy inhibition. Its effects on DENV genome replication, viral protein expression, and infectious particle production were examined by qRT-PCR, immunofluorescence imaging, flow cytometry, and plaque assays. Cytotoxicity was assessed using the MTS assay.

Results

The screen identified HM-013, a 1,4-naphthoquinone derivative structurally related to lawsone, lapachol, juglone, and plumbagin, as a potent autophagy inhibitor. HM-013 reduced autophagosome formation in a dose-dependent manner at low micromolar concentrations and significantly suppressed DENV infectious particle production. Mechanistically, HM-013 did not inhibit viral genome replication but instead blocked a late stage of the viral life cycle. The compound demonstrated low cytotoxicity in human liver and monocytic cells.

Conclusions

HM-013 is a promising autophagy inhibitor with potent anti-DENV activity and low cytotoxicity, supporting its further development as a potential dengue therapeutic.