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.

doi:10.1021/acs.jmedchem.1c00095.s001

jm1c00095_si_001.pdf (2.96 MB)

Melanocortin 1 Receptor Agonists Based on a Bivalent, Bicyclic Peptide Framework

journal contribution

posted on 2021-07-01, 20:29 authored by Thomas Durek, Quentin Kaas, Andrew M. White, Joachim Weidmann, Abdullah Ahmad Fuaad, Olivier Cheneval, Christina I. Schroeder, Simon J. de Veer, Anita Dellsén, Torben Österlund, Niklas Larsson, Laurent Knerr, Udo Bauer, Alleyn T. Plowright, David J. Craik

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; pK_i: 10.16 ± 0.04; K_i: 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.