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    
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.
Minying Cai; Magda Stankova; Dhanasekaran Muthu; Alexander Mayorov; Zhehui Yang; Devendra Trivedi; Christopher Cabello; Victor J Hruby
Related Documents :
24463069 - High-quality 3d structures shine light on antibacterial, anti-biofilm and antiviral act...
20564559 - Oxidative stress induces the formation of d-aspartyl residues in the elastin mimic pept...
22932899 - The x-ray crystal structure of human aminopeptidase n reveals a novel dimer and the bas...
25004959 - Structure determination of human fas apoptosis inhibitory molecule and identification o...
24556279 - Targeting deeper the human serum fucome by a liquid-phase multicolumn platform in combi...
23796919 - Antifungal activity of the non cytotoxic human peptide hepcidin 20 against fluconazole ...
23101989 - Structural determinants for the membrane insertion of the transmembrane peptide of hema...
11906199 - Generation of amyloid beta protein from a presenilin-1 and betaapp complex.
14706699 - The mads-box transcription factor srfa is required for actin cytoskeleton organization ...
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    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Amino Acid Sequence
Antineoplastic Agents / pharmacology*
Cell Line, Tumor / drug effects
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
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

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

Previous Document:  Spatial Variation of Available Electronic Excitations Within Individual Quantum Dots.
Next Document:  School related factors and 1yr change in physical activity amongst 9-11 year old English schoolchild...