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

Linear 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 r...

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Autores: Morais, Mauricio, Raposinho, Paula D., Oliveira, Maria Cristina, Correia, Joao D. G., Zamora-Carreras, H., Pantoja-Uceda, D., Jiménez, M. Angeles
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/162649
Acesso em linha:http://hdl.handle.net/10261/162649
Access Level:acceso abierto
Palavra-chave:alpha-MSH analogue
Cyclic peptides
Melanocortin receptor
NMR
peptide structure
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spelling NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R ReceptorMorais, MauricioRaposinho, Paula D.Oliveira, Maria CristinaCorreia, Joao D. G.Zamora-Carreras, H.Pantoja-Uceda, D.Jiménez, M. Angelesalpha-MSH analogueCyclic peptidesMelanocortin receptorNMRpeptide structureLinear 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.Peer reviewedMultidisciplinary Digital Publishing InstituteConsejo Superior de Investigaciones Científicas (España)Ministerio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201820182017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/162649reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2014-52633-Phttp://doi.org/10.3390/molecules22071189Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1626492026-05-22T06:33:51Z
dc.title.none.fl_str_mv NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
title NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
spellingShingle NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
Morais, Mauricio
alpha-MSH analogue
Cyclic peptides
Melanocortin receptor
NMR
peptide structure
title_short NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
title_full NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
title_fullStr NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
title_full_unstemmed NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
title_sort NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor
dc.creator.none.fl_str_mv Morais, Mauricio
Raposinho, Paula D.
Oliveira, Maria Cristina
Correia, Joao D. G.
Zamora-Carreras, H.
Pantoja-Uceda, D.
Jiménez, M. Angeles
author Morais, Mauricio
author_facet Morais, Mauricio
Raposinho, Paula D.
Oliveira, Maria Cristina
Correia, Joao D. G.
Zamora-Carreras, H.
Pantoja-Uceda, D.
Jiménez, M. Angeles
author_role author
author2 Raposinho, Paula D.
Oliveira, Maria Cristina
Correia, Joao D. G.
Zamora-Carreras, H.
Pantoja-Uceda, D.
Jiménez, M. Angeles
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas (España)
Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv alpha-MSH analogue
Cyclic peptides
Melanocortin receptor
NMR
peptide structure
topic alpha-MSH analogue
Cyclic peptides
Melanocortin receptor
NMR
peptide structure
description Linear 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.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/162649
url http://hdl.handle.net/10261/162649
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2014-52633-P
http://doi.org/10.3390/molecules22071189
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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