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Molecules 2017, 22(7), 1189; doi:10.3390/molecules22071189

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

1
Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela LRS, Portugal
2
Division of Imaging Sciences and Biomedical Engineering, King’s College London, 4th Floor Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK
3
Instituto de Química Física Rocasolano (IQFR), Consejo Superior de Investigaciones Científicas (CSIC), Serrano 119, 28006 Madrid, Spain
*
Author to whom correspondence should be addressed.
Received: 8 June 2017 / Revised: 12 July 2017 / Accepted: 12 July 2017 / Published: 15 July 2017
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Abstract

Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for α-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric α-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 1H and 13C 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-C6 (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. View Full-Text
Keywords: α-MSH analogue; cyclic peptide; melanocortin receptor; NMR; peptide structure α-MSH analogue; cyclic peptide; melanocortin receptor; NMR; peptide structure
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MDPI and ACS Style

Morais, M.; Zamora-Carreras, H.; Raposinho, P.D.; Oliveira, M.C.; Pantoja-Uceda, D.; Correia, J.D.G.; Jiménez, M.A. NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor. Molecules 2017, 22, 1189.

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