2. Academic Validation
  3. A Novel Class of Complement 3a Receptor Agonists and Antagonists Derived from the TLQP-21 Peptide

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. doi: 10.1021/acs.jmedchem.5c01177.
Pedro Rodriguez 1,  Jean Pierre Pallais 1,  Rongjun He 2,  Maria Razzoli 1,  John L McKee 3,  Hailey A Bock 3,  John D McCorvy 3 4,  Yuk Y Sham 1,  Richard DiMarchi 5,  Alessandro Bartolomucci 1
Affiliations

Affiliations

  • 1 Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 2 Neurocrine Biosciences, San Diego, California 92130, United States.
  • 3 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin Milwaukee, Wisconsin 53226, United States.
  • 4 Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin Milwaukee, Wisconsin 53226, United States.
  • 5 Department of Chemistry, Indiana University Bloomington, Indiana 47405, United States.
PMID: 40903728 DOI: 10.1021/acs.jmedchem.5c01177
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.

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