High-affinity cyclic peptide matriptase inhibitors

Quimbar, Pedro, Malik, Uru, Sommerhoff, Christian P., Kaas, Quentin, Chan, Lai Y., Huang, Yen-Hua, Grundhuber, Maresa, Dunse, Kerry, Craik, David J., Anderson, Marilyn A. and Daly, Norelle L. (2013) High-affinity cyclic peptide matriptase inhibitors. Journal of Biological Chemistry, 288 19: 13885-13896. doi:10.1074/jbc.M113.460030

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Author Quimbar, Pedro
Malik, Uru
Sommerhoff, Christian P.
Kaas, Quentin
Chan, Lai Y.
Huang, Yen-Hua
Grundhuber, Maresa
Dunse, Kerry
Craik, David J.
Anderson, Marilyn A.
Daly, Norelle L.
Title High-affinity cyclic peptide matriptase inhibitors
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2013-05-01
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M113.460030
Open Access Status File (Publisher version)
Volume 288
Issue 19
Start page 13885
End page 13896
Total pages 12
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
The type II transmembrane serine protease matriptase is a key activator of multiple signaling pathways associated with cell proliferation and modification of the extracellular matrix. Deregulated matriptase activity correlates with a number of diseases, including cancer and hence highly selective matriptase inhibitors may have therapeutic potential. The plant-derived cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), is a promising drug scaffold with potent matriptase inhibitory activity. In the current study we have analyzed the structure-activity relationships of SFTI-1 and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II), a structurally divergent trypsin inhibitor from Momordica cochinchinensis that also contains a cyclic backbone. We show that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, have decreased trypsin affinity, whereas several mutations either maintain or result in enhanced matriptase inhibitory activity. These intriguing results were used to design one of the most potent matriptase inhibitors known to date with a 290 pM equilibrium dissociation constant, and provide the first indication on how to modulate affinity for matriptase over trypsin in cyclic peptides. This information might be useful for the design of more selective and therapeutically relevant inhibitors of matriptase.
Keyword Molecular Modeling
Nuclear Magnetic Resonance
Peptide Conformation
Protease Inhibitor
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID SO 249/1-1
Institutional Status UQ
Additional Notes Published online: 2 April 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 44 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 23 Jun 2013, 10:22:07 EST by System User on behalf of Institute for Molecular Bioscience