Document Detail


An unusual conformation of γ-melanocyte-stimulating hormone analogues leads to a selective human melanocortin 1 receptor antagonist for targeting melanoma cells.
MedLine Citation:
PMID:  23276279     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Minying Cai; Magda Stankova; Dhanasekaran Muthu; Alexander Mayorov; Zhehui Yang; Devendra Trivedi; Christopher Cabello; Victor J Hruby
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-15
Journal Detail:
Title:  Biochemistry     Volume:  52     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-29     Completed Date:  2013-03-25     Revised Date:  2014-01-30    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  752-64     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Antineoplastic Agents / pharmacology*
Cell Line, Tumor / drug effects
Humans
Hydrogen Bonding
Inhibitory Concentration 50
Melanocyte-Stimulating Hormones / chemistry,  pharmacology
Melanoma / drug therapy*
Molecular Dynamics Simulation
Molecular Targeted Therapy
Peptides, Cyclic / pharmacology*
Protein Binding
Protein Structure, Secondary
Receptor, Melanocortin, Type 1 / antagonists & inhibitors*,  metabolism
Structure-Activity Relationship
gamma-MSH / pharmacology*
Grant Support
ID/Acronym/Agency:
DA06284/DA/NIDA NIH HHS; DK17420/DK/NIDDK NIH HHS; P01 DA006284/DA/NIDA NIH HHS; R01 DA013449/DA/NIDA NIH HHS; R01 DK017420/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Peptides, Cyclic; 0/Receptor, Melanocortin, Type 1; 0/cyclo((CH2)3-Gly-His-D-Phe-Arg-D-Trp-Cys(S-))-Asp-Arg-Phe-Gly-NH2; 0/gamma-MSH; 168482-23-3/SHU 9119; 9002-79-3/Melanocyte-Stimulating Hormones
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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