Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies.
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.
Doedens
Lucas
L
Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Opperer
Florian
F
Cai
Minying
M
Beck
Johannes G
JG
Dedek
Matt
M
Palmer
Erin
E
Hruby
Victor J
VJ
Kessler
Horst
H
D000577:Amides / Q000737:chemistry*; D001667:Binding, Competitive; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008745:Methylation; D056004:Molecular Dynamics Simulation; D009584:Nitrogen / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013379:Substrate Specificity
D000577:Amides; D010456:Peptides, Cyclic; D044102:Receptor, Melanocortin, Type 1; D043562:Receptors, G-Protein-Coupled; D009584:Nitrogen