{
  "abstract": "COVID-19 highlighted the need for antivirals that can be rapidly deployed against both current and future coronavirus threats. CMX990 is a clinical stage coronavirus main protease (Mpro) inhibitor bearing a unique trifluoromethoxymethyl ketone warhead. Here, we broadly evaluate its pan-coronavirus target engagement, antiviral breadth, and pharmacologic differentiation. Across a reporter panel of 24 Mpro enzymes spanning alpha-, beta-, delta-, and gamma-coronaviruses, CMX990 retained robust potent activity, including against nirmatrelvir-resistant SARS-CoV-2 variants. In direct comparison, nirmatrelvir and ensitrelvir showed diminished potency against non-SARS-CoV-2 coronaviruses. Live-virus assays corroborated this breadth, with potent, selective activity against SARS-CoV-2, SARS-CoV-1, MERS-CoV, and additional human coronaviruses. Structural studies revealed a conserved covalent binding mode centered on the catalytic Cys of coronavirus Mpro. In serial-passage studies, resistance emerged only after approximately twice as many serial passages under CMX990 selection as under nirmatrelvir selection, without selecting for the canonical nirmatrelvir-resistance substitution E166V. Extracellular washout experiments revealed superior persistence of antiviral activity relative to nirmatrelvir, consistent with durable target engagement. In a murine SARS-CoV-2 infection model, once-daily CMX990 protected against weight loss and reduced lung viral titers to near baseline levels. Collectively, these findings identify CMX990 as a structurally and functionally validated pan-coronavirus protease inhibitor supporting its potential as a pandemic-ready antiviral candidate.",
  "abstract_shown": true,
  "affiliations": [
    "Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, La Jolla, CA, USA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 42,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "N. G. R. D. Elshan"
    },
    {
      "name": "K. C. Wolff"
    },
    {
      "name": "L. Riva"
    },
    {
      "name": "M. A. Bakowski"
    },
    {
      "name": "S. Babarinde"
    },
    {
      "name": "A. Chaudhary"
    },
    {
      "name": "M. Zeller"
    },
    {
      "name": "A. K. Woods"
    },
    {
      "name": "G. Grabovyi"
    },
    {
      "name": "K. B. Wilson"
    },
    {
      "name": "R. A. Leonard"
    },
    {
      "name": "B. L. McGovern"
    },
    {
      "name": "J. Benjamin"
    },
    {
      "name": "I. Suazo"
    },
    {
      "name": "M. Gordon"
    },
    {
      "name": "F. O. Weiss"
    },
    {
      "name": "S. Ghorai"
    },
    {
      "name": "J. R. Pedroarena"
    },
    {
      "name": "K. L. Marquardt"
    },
    {
      "name": "M. Bimal"
    },
    {
      "name": "S. Weston"
    },
    {
      "name": "C. Dillen"
    },
    {
      "name": "A. M. Jadhav"
    },
    {
      "name": "M. G. Kirkpatrick"
    },
    {
      "name": "A. Gebara-Lamb"
    },
    {
      "name": "N. Farhat"
    },
    {
      "name": "V. T. B. Nguyen-Tran"
    },
    {
      "name": "V. Chi"
    },
    {
      "name": "K.-J. Lee"
    },
    {
      "name": "C. W. McNamara"
    },
    {
      "name": "A. K. Gupta"
    },
    {
      "name": "A. Rahimi"
    },
    {
      "name": "J. R. Teijaro"
    },
    {
      "name": "J. J. Chen"
    },
    {
      "name": "S. B. Joseph"
    },
    {
      "name": "M. Frieman"
    },
    {
      "name": "N. S. Heaton"
    },
    {
      "name": "K. White"
    },
    {
      "name": "I. A. Wilson"
    },
    {
      "name": "P. G. Schultz"
    },
    {
      "name": "S. K. Chanda"
    },
    {
      "name": "Chatt"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9fyf3z630rs42.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.29.755428",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755428v1.full",
  "id": "9fyf3z630rs42",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755428v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "2725|SARS-CoV-2 and COVID-19 Research"
    ]
  ],
  "openalex": "W7216225497",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755428v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9fyf3z630rs42.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:45Z",
      "native_id": "10.64898/2026.09.29.755428",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755428v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990",
  "title_text": "Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:45Z",
  "url": "https://research.draconitic.com/paper/9fyf3z630rs42",
  "venue": "bioRxiv",
  "versions": []
}