Rational Design of a Low Molecular Weight, Stable, Potent, and Long-Lasting GPR103 Aza-β³-pseudopeptide Agonist

Abstract

26RFa, a novel RFamide neuropeptide, is the endogenous ligand of the former orphan receptor GPR103. Intracerebroventricular injection of 26RFa and its C-terminal heptapeptide, 26RFa((20-26)), stimulates food intake in rodents. To develop potent, stable ligands of GPR103 with low molecular weight, we have designed a series of aza-β(3)-containing 26RFa((20-26)) analogues for their propensity to establish intramolecular hydrogen bonds, and we have evaluated their ability to increase [Ca(2+)](i) in GPR103-transfected cells. We have identified a compound, [Cmpi(21),aza-β(3)-Hht(23)]26RFa((21-26)), which was 8-fold more potent than 26RFa((20-26)) in mobilizing [Ca(2+)](i). This pseudopeptide was more stable in serum than 26RFa((20-26)) and exerted a longer lasting orexigenic effect in mice. This study constitutes an important step toward the development of 26RFa analogues that could prove useful for the treatment of feeding disorders.

MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

“…However, 9RFa has not been detected in tissue extracts to date. Structure-activity relationship studies have revealed that the synthetic C-terminal heptapeptide (26RFa 20-26 ; GGFSFRFamide) is responsible for the biological activity of 26RFa/QRFP (Le Marec et al 2011, Neveu et al 2012. A reverse pharmacological study has demonstrated that 26RFa/QRFP is a natural ligand for the previously identified orphan receptor, GPR103 (QRFPR), as described below (Fukusumi et al 2003, Jiang et al 2003, Takayasu et al 2006.…”

Hypothalamic QRFP: Regulation of Food Intake and Fat Selection

“…Recent investigations into the structure activity relationship of QRFP-26 and its analogues have led to the development of analogues which bind to the GPR103 receptor with high potency. Analogues of QRFP-26 (20–26) have been developed which bind with high potency to GPR103, are more stable than QRFP (20–26), more potent in mobilizing intracellular Ca + + and exert a long-lasting orexigenic effect in mice [64, 65]. The development of these analogues increases the potential for therapeutic applications in feeding-related disorders and future emphasis should be placed on determining the mechanisms by which the QRFP peptides and analogues alter the motivation to eat and other motivated behaviors.…”

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

“…The Fmoc‐amino acids carried the protection groups Cys‐Trt, Hyp‐t‐Bu, Trp‐Boc, Gln‐Trt, His‐Trt, Ser‐t‐Bu, Asp‐ O‐t‐Bu, Lys‐Boc, Glu‐O‐t‐Bu, Arg‐Pbf, Asn‐Trt, and Tyr‐t‐Bu. The Fmoc‐aza‐β 3 ‐amino acids were synthetized as previously described . The peptides were cleaved off the resin and deprotected for 4 h at room temperature with trifluoroacetic acid (TFA) (Fluorochem Ltd, Derbyshire, UK)/H 2 O/TIS (triisopropylsilane) (Aldrich) (95/2.5/2.5, 4 h) for peptides without Cys, with Cys the peptide was cleaved and deprotected with TFA/H2O/TIS/EDT (94/2.5/2.5/1, 4 h).…”