Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings.

ABSTRACT: To gain further insight into the conformational properties of small cyclic peptides that bind to the G-protein coupled receptor C5aR1, we report here for the first time the elucidation of three peptide solution conformations using residual dipolar couplings and NMR temperature coefficients. Each of these peptides varies by at least one amino acid, adopts a different intramolecular hydrogen bonding pattern, and has a different solution conformation. The solution conformations were used in combination with a homology structure of C5aR1 as a design template for increasing the potency of peptide leads for the C5a receptor. This study provides a framework for using RDC solution conformations to guide the design of peptide mimetics that emulate the target bound state in solution to minimize the strain energy of the bound conformation and improve potency of the peptide for the target.

SUBMITTER: Farley KA 

PROVIDER: S-EPMC11571007 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature