Development of novel melanocortin receptor agonists based on the cyclic peptide framework of sunflower trypsin inhibitor-1

Durek, Thomas, Cromm, Philipp M., White, Andrew M., Schroeder, Christina I., Kaas, Quentin, Weidmann, Joachim, Fuaad, Abdullah Ahmad, Cheneval, Olivier, Harvey, Peta J., Daly, Norelle L., Zhou, Yang, Dellsén, Anita, Österlund, Torben, Larsson, Niklas, Knerr, Laurent, Bauer, Udo, Kessler, Horst, Cai, Minying, Hruby, Victor J., Plowright, Alleyn T., and Craik, David J. (2018) Development of novel melanocortin receptor agonists based on the cyclic peptide framework of sunflower trypsin inhibitor-1. Journal of Medicinal Chemistry, 61 (8). pp. 3674-3684.

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Ultrastable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested toward their activity at MC1R and MC3–5R. Double N-methylated compound 18 showed a pKi of 8.73 ± 0.08 (Ki = 1.92 ± 0.34 nM) and a pEC50 of 9.13 ± 0.04 (EC50 = 0.75 ± 0.08 nM) at the human MC1R and was over 100 times more selective for MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N-methylation in shaping the conformation of the grafted pharmacophore. More broadly, this study highlights the potential of cyclic peptide scaffolds for epitope grafting in combination with N-methylation to introduce receptor subtype selectivity in the context of peptide-based drug discovery.

Item ID: 53659
Item Type: Article (Research - C1)
ISSN: 1520-4804
Copyright Information: Copyright © 2018 American Chemical Society
Funders: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC), Deutsche Forschungs-gemeinschaft (DFG)
Projects and Grants: ARC Australian Laureate Fellowship FL150100146, ARC Discovery Project grant DP150100443, NHMRC project grant APP1084604, ARC Future Fellow FT160100055, DFG Koselleck grant KE147/42-1
Date Deposited: 16 May 2018 07:41
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320506 Medical biochemistry - proteins and peptides (incl. medical proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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