{
  "abstract": "Long-acting drug–Fc conjugate (CD388) has emerged as a new class of antivirals against influenza A and B, yet the mechanisms governing how Fc conjugation reshapes small-molecule function remain undefined. Here we establish a programmable multivalent antiviral conjugates (AVCs) platform by click chemistry that enables flexible combination of valencies and conjugated drugs, allowing systematic interrogation of valency-dependent antiviral mechanisms. Using zanamivir as a model, mono-, di-, and trivalent zanamivir are conjugated with Fc, with trivalent zanamivir-Fc conjugates (AVC-Z3) exhibiting higher activity than lower-valent AVCs. AVC-Z3 induces inter-virion aggregation, thereby coupling blockade of viral entry with restriction of viral release. This cross-linking–mediated dual-stage inhibition represents a mechanistic shift from neuraminidase suppression to physical viral immobilization. Furthermore, trivalent peramivir-Fc conjugate (AVC-P3) is synthesised and exhibits stronger antiviral activity than AVC-Z3 in vitro, with much longer half-life in vivo than AVC-Z3, and CD388 with YTE mutation. The in vivo antivirus efficacy of AVC-P3 surpasses other AVCs, baloxavir, and CD388 in H1N1-, H3N2-, H5N1-, and influenza B-infection mice models. Together, our findings define ligand valency as a determinant of antiviral mechanism.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "Xun Feng"
    },
    {
      "name": "Lunzhi Yuan"
    },
    {
      "name": "Lei Zhao"
    },
    {
      "name": "Lianqi Liu"
    },
    {
      "name": "Fei Xie",
      "orcid": "0000-0001-9879-6665"
    },
    {
      "name": "Ming Zhou"
    },
    {
      "name": "Gong Cheng",
      "orcid": "0000-0001-7447-5488"
    },
    {
      "name": "Yi Guan",
      "orcid": "0000-0001-6057-9243"
    },
    {
      "name": "Ningshao Xia",
      "orcid": "0000-0003-0179-5266"
    },
    {
      "name": "Tong Cheng",
      "orcid": "0000-0002-1638-6214"
    },
    {
      "name": "Wu Zhong",
      "orcid": "0000-0002-0536-620X"
    },
    {
      "name": "Dian Xiao"
    },
    {
      "name": "Xinbo Zhou",
      "orcid": "0000-0001-8552-7757"
    },
    {
      "name": "Song Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/61g8z06wrqyg3.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-78126-3",
  "fulltext_url": "https://europepmc.org/articles/PMC13724737",
  "id": "61g8z06wrqyg3",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://www.nature.com/articles/s41467-026-78126-3",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2713|Influenza Virus Research Studies"
    ]
  ],
  "openalex": "W7218593335",
  "pdf_url": "https://www.nature.com/articles/s41467-026-78126-3_reference.pdf",
  "pmcid": "PMC13724737",
  "pmid": "42967946",
  "published": "2026-10-04",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/61g8z06wrqyg3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:38Z",
      "native_id": "10.1038/s41467-026-78126-3",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41467-026-78126-3"
    },
    {
      "first_seen": "2026-11-03T15:20:53Z",
      "native_id": "MED:42967946",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42967946"
    },
    {
      "first_seen": "2026-11-04T12:23:15Z",
      "native_id": "PMC13724737",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41467-026-78126-3"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Influenza Virus Research Studies",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses",
  "title_text": "Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:08Z",
  "url": "https://research.draconitic.com/paper/61g8z06wrqyg3",
  "venue": "Nature Communications",
  "versions": []
}