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; David J. Craik

doi:10.1021/acs.jmedchem.8b00170

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. PlowrightDavid J. Craik

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16 Scopus citations

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 pK _i of 8.73 ± 0.08 (K _i = 1.92 ± 0.34 nM) and a pEC ₅₀ of 9.13 ± 0.04 (EC ₅₀ = 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 language	English (US)
Pages (from-to)	3674-3684
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	8
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00170
State	Published - Apr 26 2018

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.8b00170

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Durek, T., Cromm, P. M., White, A. M., Schroeder, C. I., Kaas, Q., Weidmann, J., Ahmad Fuaad, A., Cheneval, O., Harvey, P. J., Daly, N. L., Zhou, Y., Dellsén, A., Österlund, T., Larsson, N., Knerr, L., Bauer, U., Kessler, H., Cai, M., Hruby, V. J., ... Craik, D. 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), 3674-3684. https://doi.org/10.1021/acs.jmedchem.8b00170

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

@article{0e892a8910fb493cba60bf414d8ab903,

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

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 pK i of 8.73 ± 0.08 (K i = 1.92 ± 0.34 nM) and a pEC 50 of 9.13 ± 0.04 (EC 50 = 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. ",

author = "Thomas Durek and Cromm, {Philipp M.} and White, {Andrew M.} and Schroeder, {Christina I.} and Quentin Kaas and Joachim Weidmann and {Ahmad Fuaad}, Abdullah and Olivier Cheneval and Harvey, {Peta J.} and Daly, {Norelle L.} and Yang Zhou and Anita Dells{\'e}n and Torben {\"O}sterlund and Niklas Larsson and Laurent Knerr and Udo Bauer and Horst Kessler and Minying Cai and Hruby, {Victor J.} and Plowright, {Alleyn T.} and Craik, {David J.}",

note = "Funding Information: This work was funded by an Australian Research Council (ARC) Australian Laureate Fellowship (FL150100146) to D.J.C., an ARC Discovery Project grant (DP150100443 awarded to D.J.C. and T.D.), and a National Health and Medical Research Council project grant (APP1084604 awarded to D.J.C, T.D., Q.K., and C.I.S). P.M.C. is thankful for a German Academic Exchange Service (DAAD) scholarship, and C.I.S. is an ARC Future Fellow (FT160100055). This work was also supported by the Deutsche Forschungs-gemeinschaft to H.K., Koselleck grant KE147/42-1. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = apr,

day = "26",

doi = "10.1021/acs.jmedchem.8b00170",

language = "English (US)",

volume = "61",

pages = "3674--3684",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "8",

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T1 - Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1

AU - Durek, Thomas

AU - Cromm, Philipp M.

AU - White, Andrew M.

AU - Schroeder, Christina I.

AU - Kaas, Quentin

AU - Weidmann, Joachim

AU - Ahmad Fuaad, Abdullah

AU - Cheneval, Olivier

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.

N1 - Funding Information: This work was funded by an Australian Research Council (ARC) Australian Laureate Fellowship (FL150100146) to D.J.C., an ARC Discovery Project grant (DP150100443 awarded to D.J.C. and T.D.), and a National Health and Medical Research Council project grant (APP1084604 awarded to D.J.C, T.D., Q.K., and C.I.S). P.M.C. is thankful for a German Academic Exchange Service (DAAD) scholarship, and C.I.S. is an ARC Future Fellow (FT160100055). This work was also supported by the Deutsche Forschungs-gemeinschaft to H.K., Koselleck grant KE147/42-1. Publisher Copyright: © 2018 American Chemical Society.

PY - 2018/4/26

Y1 - 2018/4/26

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 pK i of 8.73 ± 0.08 (K i = 1.92 ± 0.34 nM) and a pEC 50 of 9.13 ± 0.04 (EC 50 = 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 pK i of 8.73 ± 0.08 (K i = 1.92 ± 0.34 nM) and a pEC 50 of 9.13 ± 0.04 (EC 50 = 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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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -

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

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