{
  "abstract": "Selective peptide agonists for complement C5a receptor 1 (C5aR1) are valuable tools for dissecting receptor-specific inflammatory signalling, but their optimisation is complicated by overlap with closely related anaphylatoxin receptors and by pathway-dependent pharmacology. Here, we applied a structure-guided computational workflow to prioritise mutations within two C5a-derived peptide agonist scaffolds. FoldX-guided modelling identified position 5 as a candidate optimisation site, with hydrophobic substitutions predicted to improve C5aR1 engagement without corresponding gains at C3aR. Predicted BM1 and BM221 analogues were synthesised by solid-phase peptide synthesis and evaluated across C3aR, C5aR1 and C5aR2 using ERK1/2 phosphorylation and {beta}-arrestin recruitment assays. Position-5 substitutions enhanced C5aR1 functional preference in ERK assays, although additional replacement of Leu6 with Ala reduced target potency and revealed pathway-dependent receptor discrimination. BM1 P5M provided the clearest overall improvement across ERK and {beta}-arrestin readouts. In the BM221 series, A5Nle improved C5aR1 preference over C3aR, whereas A5Nle Abu6Ala produced the most favourable serum stability profile. These findings support position 5 as a transferable optimisation site and demonstrate that C5aR1 potency and receptor selectivity must be balanced during next-generation agonist design.",
  "abstract_shown": true,
  "affiliations": [
    "University of Queensland"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "J. C. Dent"
    },
    {
      "name": "X. Wu"
    },
    {
      "name": "L. Rogl"
    },
    {
      "name": "R. J. Clark"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2163nqd2jmfsp.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.02.746116",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1.full",
  "id": "2163nqd2jmfsp",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "1312|Chemical Synthesis and Analysis"
    ]
  ],
  "openalex": "W7211953225",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2163nqd2jmfsp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:12Z",
      "native_id": "10.64898/2026.09.02.746116",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Structure-Guided Design of C5aR1-Selective Peptide Agonists",
  "title_text": "Structure-Guided Design of C5aR1-Selective Peptide Agonists",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:12Z",
  "url": "https://research.draconitic.com/paper/2163nqd2jmfsp",
  "venue": "bioRxiv",
  "versions": []
}