Multiple N-Methylation of MT-II Backbone Amide Bonds Leads to Melanocortin Receptor Subtype hMC1R Selectivity: Pharmacological and Conformational Studies
| Autor: | Johannes G. Beck, Lucas Doedens, Horst Kessler, Florian Opperer, Matt Dedek, Victor J. Hruby, Erin S. Palmer, Minying Cai |
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| Rok vydání: | 2010 |
| Předmět: |
Nitrogen
Protein Conformation Stereochemistry Molecular Dynamics Simulation Binding Competitive Methylation Peptides Cyclic Biochemistry Article Catalysis Cell Line Receptors G-Protein-Coupled Substrate Specificity Colloid and Surface Chemistry Protein structure Melanocortin receptor Side chain Humans Receptor Nuclear Magnetic Resonance Biomolecular chemistry.chemical_classification General Chemistry Amides Cyclic peptide Amino acid chemistry Drug Design Melanocortin Selectivity Receptor Melanocortin Type 1 |
| Zdroj: | Journal of the American Chemical Society. 132:8115-8128 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja101428m |
| Popis: | Multiple N-methylation is a novel technology to improve bioavailability of peptides and increase receptor subtype selectivity. This technique has been applied here to the superpotent but nonselective cyclic peptide MT-II. A library of all possible 31 backbone N-methylated derivatives has been synthesized and tested for binding and activation at melanocortin receptor subtypes 1, 3, 4, and 5. It turned out that selectivity is improved with every introduced N-methyl group, resulting in several N-methylated selective and potent agonists for the hMC1R. The most potent of these derivatives is N-methylated on four out of five amide bonds in the cyclic structure. Its solution structure indicates a strongly preferred backbone conformation that resembles other alpha-MSH analogs but possesses much less flexibility and in addition distinct differences in the spatial arrangement of individual amino acid side chains. |
| Databáze: | OpenAIRE |
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