{
  "abstract": "Non-structural protein 14 (nsp14) is a bifunctional coronavirus drug target, combining a 3'-to-5' exoribonuclease domain with an N7-methyltransferase domain. Proof-of-concept data have demonstrated beneficial effects in animal models upon inhibition. Using microscale thermophoresis and X-ray crystallography, we screened full-length nsp14 for fragment hits and developed SAR-by-catalogue analogues with five- to eight-fold improved affinity. Several scaffolds showed pronounced overlap between distinct pockets, complicating structure-based optimisation. Analysis of mutational frequencies across over 14 million SARS-CoV-2 genome sequences identified nsp14 residues with markedly high and very low mutation rates, highlighting sites best suited to pan-coronavirus inhibitor design. Combining these data with all 19 publicly known fragment- and ligand-binding regions on nsp14, most of which have never been directly compared, we introduce a systematic site-naming system and rank every site by its potential for future structure-based development. Weighing criteria include proof-of-principle inhibitor data, cross-coronavirus conservation, mutation frequency, the number of fragments bound per site, and susceptibility to crystallographic artefacts from symmetry mates. This ranked, unified binding-site atlas resolves which of the many previously reported nsp14 sites merit prioritisation, providing a practical resource for future coronavirus antiviral drug development.",
  "abstract_shown": true,
  "affiliations": [
    "University College London"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "X. Shi"
    },
    {
      "name": "Q. Wang"
    },
    {
      "name": "D. Dong"
    },
    {
      "name": "M. Xu"
    },
    {
      "name": "F. Al Busaidi"
    },
    {
      "name": "M. W. Bowler"
    },
    {
      "name": "S. Haider"
    },
    {
      "affs": [
        0
      ],
      "name": "F. Kozielski"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/densd8jsgv676.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.21.760455",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760455v1.full",
  "id": "densd8jsgv676",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760455v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biochemistry"
    ],
    [
      "openalex",
      "2725|SARS-CoV-2 and COVID-19 Research"
    ]
  ],
  "openalex": "W7223220291",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760455v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-21",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/densd8jsgv676.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:12Z",
      "native_id": "10.64898/2026.10.21.760455",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760455v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2725|SARS-CoV-2 and COVID-19 Research",
      "subfield": "infectious-disease"
    }
  ],
  "title": "Mapping the Fragment-Binding Landscape of SARS-CoV-2 nsp14 for Antiviral Drug Discovery",
  "title_text": "Mapping the Fragment-Binding Landscape of SARS-CoV-2 nsp14 for Antiviral Drug Discovery",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:12Z",
  "url": "https://research.draconitic.com/paper/densd8jsgv676",
  "venue": "bioRxiv",
  "versions": []
}