A Novel Class of Complement 3a Receptor Agonists and Antagonists Derived from the TLQP-21 Peptide. J Med Chem 2025 Sep 25;68(18):19107-19121
Date
09/04/2025Pubmed ID
40903728Pubmed Central ID
PMC12481481DOI
10.1021/acs.jmedchem.5c01177Scopus ID
2-s2.0-105017063461 (requires institutional sign-in at Scopus site)Abstract
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.
Author List
Rodriguez P, Pallais JP, He R, Razzoli M, McKee JL, Bock HA, McCorvy JD, Sham YY, DiMarchi R, Bartolomucci AAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsHEK293 Cells
Humans
Peptide Fragments
Receptors, Complement
Structure-Activity Relationship
