Development of Potent and Selective Agonists for Complement C5a Receptor 1 with In Vivo Activity

The
anaphylatoxin C5a is a complement peptide associated with immune-related
disorders. C5a binds with equal potency to two GPCRs, C5aR1 and C5aR2.
Multiple C5a peptide agonists have been developed to interrogate the
C5a receptor function but none show selectivity for C5aR1. To address
these limitations, we developed potent and stable peptide C5aR1 agonists
that display no C5aR2 activity and over 1000-fold selectivity for
C5aR1 over C3aR. This includes BM213, which induces C5aR1-mediated
calcium mobilization and pERK1/2 signaling but not β-arrestin
recruitment, and BM221, which exhibits no signaling bias. Both ligands
are functionally similar to C5a in human macrophage cytokine release
assays and in a murine in vivo neutrophil mobilization assay. BM213
showed antitumor activity in a mouse model of mammary carcinoma. We
anticipate that these C5aR1-selective agonists will be useful research
tools to investigate C5aR1 function.