{
  "abstract": "Lysine-directed covalent liganding offers a promising strategy to expand the covalently ligandable proteome beyond cysteine. However, broadly applicable and selective lysine-reactive scaffolds remain limited. Here, we designed SCL-alkyne, a simplified azaphilone probe derived from the natural product sclerotiorin (SCL), for the global profiling of lysine reactivity in bacteria. SCL-alkyne displayed high intrinsic selectivity for lysine in vitro and in live Escherichia coli cells. In situ proteome profiling revealed that 84% of engaged sites belong to lysine residues and the protein N-terminus. Reactivity mapping provided an inventory of highly reactive sites showing that only a limited subset of reactive lysines is located in functional regions of proteins. Analysis of proteins enriched via the SCL-alkyne probe unraveled bacterial chemotaxis as a major target pathway which was confirmed by an impaired chemotactic response upon treatment of bacteria with SCL-alkyne. Competitive profiling of three structurally related azaphilone natural products identified 60 protein targets belonging to pathways related to iron-sulfur cluster assembly and antioxidant function. This study not only highlights the diverse modes-of-action of natural product azaphilones, but also establishes its core scaffold as effective lysine-reactive chemotype for identifying ligandable lysines.",
  "abstract_shown": true,
  "affiliations": [
    "TU Munich"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "W. Ding"
    },
    {
      "name": "S. Brameyer"
    },
    {
      "name": "S. H. Kirsch"
    },
    {
      "name": "B. Sandargo"
    },
    {
      "name": "F. Surup"
    },
    {
      "name": "S. M. Hacker"
    },
    {
      "name": "K. Jung"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Sieber"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5frb7xz2k3em9.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.27.751175",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.27.751175v1.full",
  "id": "5frb7xz2k3em9",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.27.751175v1",
  "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",
      "biochemistry"
    ],
    [
      "openalex",
      "1605|Click Chemistry and Applications"
    ]
  ],
  "openalex": "W7214646040",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.27.751175v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5frb7xz2k3em9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:54Z",
      "native_id": "10.64898/2026.09.27.751175",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.27.751175v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Click Chemistry and Applications",
      "subfield": "organic"
    }
  ],
  "title": "Natural product-derived azaphilones are selective scaffolds for covalent lysine liganding in live cells",
  "title_text": "Natural product-derived azaphilones are selective scaffolds for covalent lysine liganding in live cells",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:54Z",
  "url": "https://research.draconitic.com/paper/5frb7xz2k3em9",
  "venue": "bioRxiv",
  "versions": []
}