Solid-phase peptide head-to-side chain cyclodimerization: Discovery of C2-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors

Abstract

A novel hybrid melanocortin pharmacophore was designed based on the pharmacophores of the Agouti signaling protein (ASIP), an endogenous melanocortin antagonist, and α-melanocytestimulating hormone (α-MSH), an endogenous melanocortin agonist. The designed hybrid ASIP/ MSH pharmacophore was explored in monomeric cyclic, and cyclodimeric templates. The monomeric cyclic disulfide series yielded peptides with hMC3R-selective non-competitive binding affinities. The direct on-resin peptide lactam cyclodimerization yielded nanomolar range (25-120 nM) hMC1R-selective full and partial agonists in the cyclodimeric lactam series which demonstrates an improvement over the previous attempts at hybridization of MSH and agouti protein sequences. The secondary structure-oriented pharmacophore hybridization strategy will prove useful in development of unique allosteric and orthosteric melanocortin receptor modulators. This report also illustrates the utility of peptide cyclodimerization for the development of novel GPCR peptide ligands.

Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2

“…A chimeric NDP-MSH/AGRP peptide, Ac-Ser-Tyr-Ser-Nle-Glu-His-Arg-Phe-Phe-Gly-Lys-Pro-Val-NH 2 , is a more potent stimulator for the mMC3R over the mMC4R (EC 50 = 480 vs 930 nM) . Moreover, a series of disulfide cyclized chimeric α-MSH/ASIP analogues, template Ac-c­[Cys-Arg-(X)­Phe-Cys]-(X)­Trp-NH 2 , where X is d or l stereochemistry, are reported to possess hMC3R-selective noncompetitive binding . The unusual sequence of the TACO scaffold with respect to the endogenous “His-Phe-Arg-Trp” and “Arg-Phe-Phe” sequences gives additional insights into the requirements for receptor recognition and selectivity for the melanocortin subtypes.…”

Targeting protein−protein interfaces using macrocyclic peptides

“…In term of their functions, macrocyclic peptide PPI regulators can be generally described as activators and inhibitors. An activator can facilitate protein−protein associations, thereby increasing the PPI‐mediated cellular response. For example, peptide A (Figure ) was found to activate human melanocortin 3 receptor (hMC3R), an inhibitory autoreceptor on the surface of proopiomelanocortin neurons .…”

“…An activator can facilitate protein−protein associations, thereby increasing the PPI‐mediated cellular response. For example, peptide A (Figure ) was found to activate human melanocortin 3 receptor (hMC3R), an inhibitory autoreceptor on the surface of proopiomelanocortin neurons . Meanwhile, the macrocyclic peptide inhibitors suppress the PPI‐induced response by disrupting the protein−protein complex formation.…”

Morphological transition triggered by mannose conjugation to a cyclic hexapeptide

“…14 Cyclodimerization had been employed in some cases, but mostly cyclization steps involved disulfide bond formation, 15 depsipeptide formation, 16 click reaction to form triazole, 17 unnatural amino acids, 18 side chains (lysine, glutamic acid) of natural amino acids, 14 metal ions as templates, 19 and peptide containing thiazole ring in side chain.…”