A Novel Class of Complement 3a Receptor Agonists and Antagonists Derived from the TLQP-21 Peptide
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.
Authors
- Pedro Rodríguez (ORCID: https://orcid.org/0000-0002-4993-079X)
- Yuk Y. Sham (ORCID: https://orcid.org/0000-0003-2601-8930)
- Rongjun He (ORCID: https://orcid.org/0000-0001-9093-5165)
- Maria Razzoli (ORCID: https://orcid.org/0000-0001-5911-4633)
- Jean Pierre Pallais (ORCID: https://orcid.org/0000-0003-1111-8031)
- Hailey A. Bock
- John D. McCorvy (ORCID: https://orcid.org/0000-0001-7555-9413)
- Alessandro Bartolomucci (ORCID: https://orcid.org/0000-0001-6439-8829)
- Richard D. DiMarchi (ORCID: https://orcid.org/0000-0003-0220-4085)
- J. M. T. McKee (ORCID: https://orcid.org/0009-0003-7988-8646)
Institutions
- University of Minnesota (US)
- Medical College of Wisconsin (US)
- University of Minnesota System (US)
- Indiana University Bloomington (US)
- Institute of Cell Biology and Neurobiology (IT)
- Institute of Pharmacology (CZ)
- Indiana University (US)
- Neurocrine Biosciences (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01177
- Citations
- 2
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Clinical and Translational Science Institute, University of Minnesota
- National Institute of Mental Health
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases