6BVU

SFTI-HFRW-1

6BVU の概要

• エントリーDOI: 10.2210/pdb6bvu/pdb
• NMR情報: BMRB: 30380
• 分子名称: Trypsin inhibitor 1 HFRW-1 (1 entity in total)
• 機能のキーワード: biosynthetic protein
• 由来する生物種: Helianthus annuus (common sunflower)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1690.02

構造登録者

Schroeder, C.I. (登録日: 2017-12-13, 公開日: 2018-12-19, 最終更新日: 2024-11-06)

主引用文献

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

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: 29605997
DOI: 10.1021/acs.jmedchem.8b00170

実験手法

SOLUTION NMR