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). pp. 13885-13896.

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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.

Item ID: 26983
Item Type: Article (Research - C1)
ISSN: 1083-351X
Keywords: molecular modeling, nuclear magnetic resonance, peptide conformation, peptides, protease inhibitor
Date Deposited: 20 May 2013 06:37
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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