DArg10_Aib20

The complement 3a receptor (C3aR) is a G-protein-coupled receptor (GPCR) involved in inflammatory, metabolic, and neurological diseases. Two endogenous ligands (C3a and TLQP-21) and small molecules (SB290157 and JR14a) differentially signal at C3aR, but these properties are not fully understood and need to be optimized with medicinal chemistry. Here, we generated rationally designed peptidergic analogues of TLQP-21 in an effort to extend the range of compounds with therapeutic potential beyond C3a-derived peptidergic agonists or small-molecule antagonists. We identified key arginines in the central portion of the peptide and the C-terminus, where mutation confers enhanced plasma stability. Mutations at the C-terminal motif alanine-arginine (-AlaArg), with unnatural amino acids and stereoisomers conferred signaling selectivity, enhanced peptide potency (e.g., DArg10_DAla20), or resulted in a functional antagonist (DArg10_Aib20). Overall, we increased our understanding of the C3aR mechanism of action, expanding and differentiating the range of therapeutic potentials for this GPCR.