Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1

Thomas Durek, Philipp M. Cromm, Andrew M. White, Christina I. Schroeder, Quentin Kaas, Joachim Weidmann, Abdullah Ahmad Fuaad, Olivier Cheneval, Peta J. Harvey, Norelle L. Daly, Yang Zhou, Anita Dellsén, Torben Österlund, Niklas Larsson, Laurent Knerr, Udo Bauer, Horst Kessler, Minying Cai, Victor J Hruby, Alleyn T. Plowright & 1 others David J. Craik

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3674-3684
Number of pages11
JournalJournal of Medicinal Chemistry
Volume61
Issue number8
DOIs
StatePublished - Apr 26 2018

Fingerprint

Melanocortin Receptors
Cyclic Peptides
Methylation
Peptides
Drug Design
Drug Discovery
Biological Availability
Epitopes
Magnetic Resonance Spectroscopy
sunflower SFTI-1 peptide

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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; Ahmad Fuaad, Abdullah; 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.; Craik, David J.

In: Journal of Medicinal Chemistry, Vol. 61, No. 8, 26.04.2018, p. 3674-3684.

Research output: Contribution to journalArticle

Durek, T, Cromm, PM, White, AM, Schroeder, CI, Kaas, Q, Weidmann, J, Ahmad Fuaad, A, Cheneval, O, Harvey, PJ, Daly, NL, Zhou, Y, Dellsén, A, Österlund, T, Larsson, N, Knerr, L, Bauer, U, Kessler, H, Cai, M, Hruby, VJ, Plowright, AT & Craik, DJ 2018, 'Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1', Journal of Medicinal Chemistry, vol. 61, no. 8, pp. 3674-3684. https://doi.org/10.1021/acs.jmedchem.8b00170
Durek, Thomas ; Cromm, Philipp M. ; White, Andrew M. ; Schroeder, Christina I. ; Kaas, Quentin ; Weidmann, Joachim ; Ahmad Fuaad, Abdullah ; 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. ; Craik, David J. / Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 8. pp. 3674-3684.
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abstract = "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.",
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AU - Kaas, Quentin

AU - Weidmann, Joachim

AU - Ahmad Fuaad, Abdullah

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AU - Harvey, Peta J.

AU - Daly, Norelle L.

AU - Zhou, Yang

AU - Dellsén, Anita

AU - Österlund, Torben

AU - Larsson, Niklas

AU - Knerr, Laurent

AU - Bauer, Udo

AU - Kessler, Horst

AU - Cai, Minying

AU - Hruby, Victor J

AU - Plowright, Alleyn T.

AU - Craik, David J.

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N2 - 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.

AB - 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.

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