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NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor

AutorMorais, Mauricio; Raposinho, Paula D.; Oliveira, Maria Cristina; Correia, Joao D. G.; Zamora-Carreras, H.; Pantoja-Uceda, D.; Jiménez, M. Angeles
Palabras clavealpha-MSH analogue
cyclic peptide
melanocortin receptor
peptide structure
Fecha de publicaciónjul-2017
EditorMultidisciplinary Digital Publishing Institute
CitaciónMolecules 22(7): 1189 (2017)
ResumenLinear and cyclic analogues of the alpha-melanocyte stimulating hormone (alpha-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of alpha-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for alpha-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric alpha-MSH analogues, c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH2 (CycN-K6) and c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH2 (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by H-1 and C-13 NMR. These results were compared to those of the previously reported analogue c[S-NO2-C6H3-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH2 (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 +/- 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 +/- 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C-6 (IC50 = 1770 +/- 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle's side chains are favorably positioned for receptor interaction.
Versión del editorhttp://doi.org/10.3390/molecules22071189
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