6BVW
SFTI-HFRW-3
Summary for 6BVW
| Entry DOI | 10.2210/pdb6bvw/pdb |
| NMR Information | BMRB: 30381 |
| Descriptor | Trypsin inhibitor 1 HFRW-3 (1 entity in total) |
| Functional Keywords | melanocortin, pharmacophore, cyclic peptide, biosynthetic protein |
| Biological source | Helianthus annuus (common sunflower) |
| Total number of polymer chains | 1 |
| Total formula weight | 1717.07 |
| Authors | Schroeder, C.I. (deposition date: 2017-12-14, release date: 2018-12-19, Last modification date: 2023-11-15) |
| Primary citation | 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.,Dellsen, A.,Osterlund, T.,Larsson, N.,Knerr, L.,Bauer, U.,Kessler, H.,Cai, M.,Hruby, V.J.,Plowright, A.T.,Craik, D.J. Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1. J.Med.Chem., 61:3674-3684, 2018 Cited by PubMed 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 p K of 8.73 ± 0.08 ( K = 1.92 ± 0.34 nM) and a pEC of 9.13 ± 0.04 (EC = 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. PubMed: 29605997DOI: 10.1021/acs.jmedchem.8b00170 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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