{
  "id": 6329393,
  "title": "Structure-Guided Design of C5aR1-Selective Peptide Agonists",
  "url": "https://urgent.news/2026/09/08/structure-guided-design-of-c5ar1-selective-peptide-agonists",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-08T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1?rss=1"
  },
  "original_language": "en",
  "account": "Selective peptide agonists targeting complement C5a receptor 1 (C5aR1) are essential for studying receptor-specific inflammatory signaling, although their optimization is challenging due to similarities with related anaphylatoxin receptors and pathway-dependent pharmacology. In this study, a structure-guided computational workflow was employed to prioritize mutations within two C5a-derived peptide agonist scaffolds. Using FoldX-guided modeling, position 5 was identified as a potential optimization site, with hydrophobic substitutions predicted to improve C5aR1 engagement without significant impact on C3aR binding. Predicted BM1 and BM221 analogues were synthesized via solid-phase peptide synthesis and evaluated for their effects on C3aR, C5aR1, and C5aR2 using ERK1/2 phosphorylation and β-arrestin recruitment assays. Position-5 substitutions demonstrated enhanced functional preference for C5aR1 in ERK assays, although the replacement of Leu6 with Ala reduced target potency, indicating pathway-dependent receptor discrimination. The BM1 P5M substitution showed the greatest overall improvement across ERK and β-arrestin readouts. In the BM221 series, A5Nle substitution improved C5aR1 preference over C3aR, while A5Nle Abu6Ala produced the most favorable serum stability profile. These findings suggest that position 5 is a transferable optimization site and emphasize the need to balance C5aR1 potency and receptor selectivity during the design of next-generation agonists.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}