title: An unusual conformation of γ-melanocyte-stimulating hormone analogues leads to a selective human melanocortin 1 receptor antagonist for targeting melanoma cells.
abstract: γ-MSH (γ-melanocyte-stimulating hormone, H-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-OH), with its exquisite specificity and potency, has recently created much excitement as a drug lead. However, this peptide is like most peptides susceptible to proteolysis in vivo, which potentially decreases its beneficial activities. In our continued effort to design a proteolytically stable ligand with specific receptor binding, we have engineered peptides by cyclizing γ-MSH using a thioether bridge. A number of novel cyclic truncated γ-MSH analogues were designed and synthesized, in which a thioether bridge was incorporated between a cysteine side chain and an N-terminal bromoacyl group. One of these peptides, cyclo-[(CH(2))(3)CO-Gly(1)-His(2)-D-Phe(3)-Arg(4)-D-Trp(5)-Cys(S-)(6)]-Asp(7)-Arg(8)-Phe(9)-Gly(10)-NH(2), demonstrated potent antagonist activity and receptor selectivity for the human melanocortin 1 receptor (hMC1R) (IC(50) = 17 nM). This novel peptide is the most selective antagonist for the hMC1R to date. Further pharmacological studies have shown that this peptide can specifically target melanoma cells. The nuclear magnetic resonance analysis of this peptide in a membrane-like environment revealed a new turn structure, specific to the hMC1R antagonist, at the C-terminus, where the side chain and backbone conformation of D-Trp(5) and Phe(9) of the peptide contribute to hMC1R selectivity. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.
authors.affiliation: Department of Chemistry and Biochemistry, 1306 East University Boulevard, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Magda
authors.initials: M
authors.lastname: Stankova
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Muthu
authors.forename: Alexander
authors.initials: A
authors.lastname: Mayorov
authors.forename: Zhehui
authors.initials: Z
authors.lastname: Yang
authors.forename: Devendra
authors.initials: D
authors.lastname: Trivedi
authors.forename: Christopher
authors.initials: C
authors.lastname: Cabello
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy*; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D044102:Receptor, Melanocortin, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D019825:gamma-MSH / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D044102:Receptor, Melanocortin, Type 1; C579091:cyclo((CH2)3-Gly-His-D-Phe-Arg-D-Trp-Cys(S-))-Asp-Arg-Phe-Gly-NH2; D019825:gamma-MSH; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones