Your browser doesn't support javascript.
loading
Melanocortin 1 Receptor Agonists Based on a Bivalent, Bicyclic Peptide Framework.
Durek, Thomas; Kaas, Quentin; White, Andrew M; Weidmann, Joachim; Fuaad, Abdullah Ahmad; Cheneval, Olivier; Schroeder, Christina I; de Veer, Simon J; Dellsén, Anita; Österlund, Torben; Larsson, Niklas; Knerr, Laurent; Bauer, Udo; Plowright, Alleyn T; Craik, David J.
Afiliação
  • Durek T; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Kaas Q; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • White AM; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Weidmann J; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Fuaad AA; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Cheneval O; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Schroeder CI; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • de Veer SJ; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
  • Dellsén A; Mechanistic Biology & Profiling, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
  • Österlund T; Discovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
  • Larsson N; Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
  • Knerr L; Discovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
  • Bauer U; Medicinal Chemistry, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
  • Plowright AT; Medicinal Chemistry, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
  • Craik DJ; Medicinal Chemistry, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg 43183, Mölndal, Sweden.
J Med Chem ; 64(14): 9906-9915, 2021 07 22.
Article em En | MEDLINE | ID: mdl-34197114
ABSTRACT
We have designed a new class of highly potent bivalent melanocortin receptor ligands based on the nature-derived bicyclic peptide sunflower trypsin inhibitor 1 (SFTI-1). Incorporation of melanotropin pharmacophores in each of the two turn regions of SFTI-1 resulted in substantial gains in agonist activity particularly at human melanocortin receptors 1 and 3 (hMC1R/hMC3R) compared to monovalent analogues. In in vitro binding and functional assays, the most potent molecule, compound 6, displayed low picomolar agonist activity at hMC1R (pEC50 > 10.3; EC50 < 50 pM; pKi 10.16 ± 0.04; Ki 69 ± 5 pM) and is at least 30-fold more selective for this receptor than for hMC3R, hMC4R, or hMC5R. The results are discussed in the context of structural homology models of hMCRs in complex with the developed bivalent ligands.
Assuntos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos Cíclicos / Receptor Tipo 1 de Melanocortina Limite: Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos Cíclicos / Receptor Tipo 1 de Melanocortina Limite: Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália