{
  "abstract": "Background: Dengue virus (DENV) infection remains a global health threat with no approved small-molecule antiviral for clinical use. Luteolin, a natural flavonoid, exhibits anti-dengue activity but suffers from poor solubility and moderate potency. The 7-O position is the primary site of metabolic glucuronidation, whereas the 5-O position is sequestered by intramolecular hydrogen bonding, offering structurally distinct positions for derivatization.\n\nMethods: Five site-selective derivatives of luteolin (three 5-O- and two 7-O-substituted) were synthesized. Their anti-DENV activity was evaluated in Vero cells by qRT-PCR (measuring viral RNA abundance) and plaque assays, and cytotoxicity was determined using the CCK8 method. For mechanistic exploration, enzymatic inhibition kinetics against NS2B/NS3 and furin were measured, and target engagement was further assessed via molecular docking and cellular thermal shift assays (CETSA).\n\nResults: Among the derivatives, compound 5, bearing a 4-fluorobenzenesulfonyl group at the 7-O position, exhibited the most potent anti-DENV activity (EC ₅₀ = 0.46 μM) and the highest selectivity index (SI = 28.5), representing an 18-fold increase in antiviral potency over luteolin. In enzymatic assays, compound 5 showed preferential inhibition of the viral NS2B/NS3 protease ( K i = 11.54 μM) over the host furin ( K i = 93 μM). Molecular docking and thermal stabilization assays provided correlative evidence supporting target engagement with both proteases.\n\nConclusion: Site-selective 7-O-sulfonation of luteolin yields compound 5, a derivative with improved anti-DENV activity and selectivity that shows preferential NS2B/NS3 inhibition in enzymatic assays. This study provides a structural framework for the further optimization of flavonoid-based antiviral agents.",
  "abstract_shown": true,
  "affiliations": [
    "Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou , ,",
    "Chinese Medicine Guangdong Laboratory, Hengqin , ,",
    "School of Medicine, The Sixth Affiliated Hospital of South China University of Technology (Nanhai District People’s Hospital of Foshan), Foshan , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Huini Chen"
    },
    {
      "affs": [
        1
      ],
      "name": "Zizhao Lao"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuhang Huo"
    },
    {
      "affs": [
        0
      ],
      "name": "Liangwen Yu"
    },
    {
      "affs": [
        2
      ],
      "name": "Wen Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Geng Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cc1rrwg03gq3q.bib",
  "cited_by": 0,
  "doi": "10.3389/fmicb.2026.1931544",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672209/?tool=EBI",
  "id": "cc1rrwg03gq3q",
  "issns": [
    "1664-302X"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13672209",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2739|Mosquito-borne diseases and control"
    ]
  ],
  "openalex": "W7215040936",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672209/pdf/?tool=EBI",
  "pmcid": "PMC13672209",
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/cc1rrwg03gq3q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:18Z",
      "native_id": "PMC:PMC13672209",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13672209"
    },
    {
      "first_seen": "2026-10-30T12:19:12Z",
      "native_id": "10.3389/fmicb.2026.1931544",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fmicb.2026.1931544/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2739|Mosquito-borne diseases and control",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "7-O-sulfonation redirects luteolin’s target preference from furin to NS2B/NS3 and enhances anti-dengue activity",
  "title_text": "7-O-sulfonation redirects luteolin’s target preference from furin to NS2B/NS3 and enhances anti-dengue activity",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:12Z",
  "url": "https://research.draconitic.com/paper/cc1rrwg03gq3q",
  "venue": "Frontiers in microbiology",
  "versions": []
}