6bvu

SFTI-HFRW-1SFTI-HFRW-1

Structural highlights

6bvu is a 1 chain structure with sequence from Helianthus annuus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SFTI1_HELAN Inhibits trypsin, cathepsin G, elastase, chymotrypsin and thrombin. Does not inhibit factor Xa.^[1]

Publication Abstract from PubMed

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 Ki 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.

Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1.,Durek T, Cromm PM, White AM, Schroeder CI, Kaas Q, Weidmann J, Ahmad Fuaad A, Cheneval O, Harvey PJ, Daly NL, Zhou Y, Dellsen A, Osterlund T, Larsson N, Knerr L, Bauer U, Kessler H, Cai M, Hruby VJ, Plowright AT, Craik DJ J Med Chem. 2018 Apr 11. doi: 10.1021/acs.jmedchem.8b00170. PMID:29605997^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL. High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds. J Mol Biol. 1999 Jul 9;290(2):525-33. PMID:10390350 doi:10.1006/jmbi.1999.2891
↑ Durek T, Cromm PM, White AM, Schroeder CI, Kaas Q, Weidmann J, Ahmad Fuaad A, Cheneval O, Harvey PJ, Daly NL, Zhou Y, Dellsen A, Osterlund T, Larsson N, Knerr L, Bauer U, Kessler H, Cai M, Hruby VJ, Plowright AT, Craik DJ. Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1. J Med Chem. 2018 Apr 11. doi: 10.1021/acs.jmedchem.8b00170. PMID:29605997 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00170

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OCA

[1] Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL. High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds. J Mol Biol. 1999 Jul 9;290(2):525-33. PMID:10390350 doi:10.1006/jmbi.1999.2891

[2] Durek T, Cromm PM, White AM, Schroeder CI, Kaas Q, Weidmann J, Ahmad Fuaad A, Cheneval O, Harvey PJ, Daly NL, Zhou Y, Dellsen A, Osterlund T, Larsson N, Knerr L, Bauer U, Kessler H, Cai M, Hruby VJ, Plowright AT, Craik DJ. Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1. J Med Chem. 2018 Apr 11. doi: 10.1021/acs.jmedchem.8b00170. PMID:29605997 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00170

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