{
  "abstract": "The SARS-CoV-2 spike protein binds its receptor ACE2 to initiate target-cell infection. To engage ACE2, at least one of the three receptor-binding domains (RBDs) of the spike must adopt the up orientation. Here, we describe S22, a potent, bioavailable, and non-toxic inhibitor of BA.2 and all subsequent Omicron variants. Cryo-EM analyses showed that S22 assembled as a trimer in the central cavity of the spike apex, stabilizing all three RBDs in the down orientation, thereby preventing ACE2 association. Binding studies, especially those using mixed S22-sensitive and -resistant spikes, imply a cooperative assembly of three S22 molecules with three RBDs, resulting in an unusually slow S22 off-rate. Consistent with its slow dissociation and favorable pharmacokinetics, S22 suppressed viral replication and inflammation in the lungs of XBB.1.5-infected female mice. Thus, S22 potently inhibits Omicron entry through a distinct mechanism whereby a small compound assembles cooperatively as a trimer to stabilize spike in an inactive conformation.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
      "name": "Huihui Mou"
    },
    {
      "name": "Bo Gao",
      "orcid": "0000-0003-4787-594X"
    },
    {
      "name": "Gang Ye",
      "orcid": "0000-0001-6034-2174"
    },
    {
      "name": "Divyasha Saxena"
    },
    {
      "name": "Lizhou Zhang",
      "orcid": "0000-0002-2637-9712"
    },
    {
      "name": "Fan Bu",
      "orcid": "0000-0002-6965-3072"
    },
    {
      "name": "Jyoti Vishwakarma"
    },
    {
      "name": "Yulia Getmanenko"
    },
    {
      "name": "Shuo Zhou",
      "orcid": "0000-0001-8684-8341"
    },
    {
      "name": "Claudia Ruiz Bayona"
    },
    {
      "name": "Li Lin"
    },
    {
      "name": "Janarjan Bhandari",
      "orcid": "0000-0002-3900-9067"
    },
    {
      "name": "Charles C. Bailey"
    },
    {
      "name": "Gogce C. Crynen"
    },
    {
      "name": "Claire E. Kitzmiller",
      "orcid": "0009-0001-7069-4891"
    },
    {
      "name": "Hao Li"
    },
    {
      "name": "Yuka Otsuka",
      "orcid": "0000-0003-3739-5790"
    },
    {
      "name": "Lalit Batra",
      "orcid": "0000-0002-4375-9004"
    },
    {
      "name": "Stuart Weston",
      "orcid": "0000-0001-9840-2953"
    },
    {
      "name": "Matthew B. Frieman",
      "orcid": "0000-0003-0107-0775"
    },
    {
      "name": "David K. Meyerholz",
      "orcid": "0000-0003-1552-3253"
    },
    {
      "name": "Louis Scampavia"
    },
    {
      "name": "Timothy P. Spicer",
      "orcid": "0000-0002-9080-4226"
    },
    {
      "name": "Reuben S. Harris",
      "orcid": "0000-0002-9034-9112"
    },
    {
      "name": "Michael D. Cameron",
      "orcid": "0000-0003-3154-4775"
    },
    {
      "name": "Thomas D. Bannister",
      "orcid": "0000-0003-0683-8886"
    },
    {
      "name": "Jian Zheng"
    },
    {
      "name": "Michael Farzan",
      "orcid": "0000-0002-2990-5319"
    },
    {
      "name": "Fang Li",
      "orcid": "0000-0002-1958-366X"
    },
    {
      "name": "Hyeryun Choe",
      "orcid": "0000-0003-4538-7176"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8fhn7fr6xjnb4.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-78835-9",
  "fulltext_url": null,
  "id": "8fhn7fr6xjnb4",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://www.nature.com/articles/s41467-026-78835-9",
  "language": null,
  "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": [
    [
      "openalex",
      "2725|SARS-CoV-2 and COVID-19 Research"
    ]
  ],
  "openalex": "W7223856826",
  "pdf_url": "https://www.nature.com/articles/s41467-026-78835-9_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/8fhn7fr6xjnb4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:39Z",
      "native_id": "10.1038/s41467-026-78835-9",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41467-026-78835-9"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|SARS-CoV-2 and COVID-19 Research",
      "subfield": "infectious-disease"
    }
  ],
  "title": "A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation",
  "title_text": "A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:39Z",
  "url": "https://research.draconitic.com/paper/8fhn7fr6xjnb4",
  "venue": "Nature Communications",
  "versions": []
}