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Updated: Jun 7, 2025
07:11
Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
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Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings
Kathleen A Farley1, Ye Che1, Ricardo Lira1
1Medicine Design, Pfizer Inc., 445 Eastern Point Rd, Groton, Connecticut 06340, United States.
ACS Medicinal Chemistry Letters
|November 20, 2024
Summary
Researchers uncovered three distinct solution conformations for cyclic peptides targeting the C5a receptor (C5aR1). This conformational data guides the design of more potent peptide therapeutics by mimicking the target-bound state.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Pharmacology
Background:
- G-protein coupled receptors (GPCRs) are crucial drug targets.
- Small cyclic peptides are emerging as potent modulators of GPCRs.
- Understanding peptide conformation is key to optimizing drug design.
Purpose of the Study:
- To elucidate the solution conformations of cyclic peptides binding to the C5a receptor 1 (C5aR1).
- To utilize these conformations for designing more potent peptide-based therapeutics.
- To establish a framework for structure-based peptide drug design.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy.
- Residual dipolar couplings (RDCs) for structural determination.
- NMR temperature coefficients to identify hydrogen bonding patterns.
Main Results:
- Three unique solution conformations were determined for distinct cyclic peptides.
- Each peptide exhibited a different intramolecular hydrogen bonding pattern.
- Conformational insights were applied to design more potent C5aR1-targeting peptides.
Conclusions:
- Solution conformations of cyclic peptides can be accurately determined using RDCs and NMR temperature coefficients.
- This approach provides a valuable framework for structure-guided design of peptide mimetics.
- Minimizing bound state strain energy through conformational design enhances peptide potency.
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