Structure-Guided Design of C5aR1-Selective Peptide Agonists
- 1University of Queensland
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.
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BibTeX
@misc{dent2026structureguided,
title = {{Structure-Guided Design of C5aR1-Selective Peptide Agonists}},
author = {J. C. Dent and X. Wu and L. Rogl and R. J. Clark},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.746116},
url = {https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structure-Guided Design of C5aR1-Selective Peptide Agonists
AU - J. C. Dent
AU - X. Wu
AU - L. Rogl
AU - R. J. Clark
PY - 2026
DA - 2026/09/02
PB - bioRxiv
DO - 10.64898/2026.09.02.746116
UR - https://www.biorxiv.org/content/10.64898/2026.09.02.746116v1
AB - 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.
ER -