Dataset Information

Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II.

ABSTRACT: Kallikrein-related peptidase 4 (KLK4) is a serine protease that has putative intracellular and extracellular functions in prostate cancer progression. Here we show that MCoTI-II, a 34-amino acid cyclic peptide found in the seeds of red gac (Momordica cochinchinensis), is an inhibitor of KLK4. By grafting a preferred KLK4 cleavage sequence into MCoTI-II, we produced a highly potent KLK4 inhibitor (K i = 0.1 nM) that displayed 100,000-fold selectivity over related KLKs and the ability to penetrate cells. Additionally, by substituting positively charged noncontact residues in this compound, we produced a potent and selective KLK4 inhibitor that does not penetrate cells. The inhibitors were shown to be nontoxic to human cells and stable in human serum. These KLK4 inhibitors provide useful chemical tools to further define the role(s) of both intracellular and extracellular KLK4 in prostate cancer cell lines and disease models.

SUBMITTER: Swedberg JE

PROVIDER: S-EPMC6295872 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II.

Swedberg Joakim E JE Ghani Hafiza Abdul HA Harris Jonathan M JM de Veer Simon J SJ Craik David J DJ

ACS medicinal chemistry letters 20181121 12

Kallikrein-related peptidase 4 (KLK4) is a serine protease that has putative intracellular and extracellular functions in prostate cancer progression. Here we show that MCoTI-II, a 34-amino acid cyclic peptide found in the seeds of red gac (Momordica cochinchinensis), is an inhibitor of KLK4. By grafting a preferred KLK4 cleavage sequence into MCoTI-II, we produced a highly potent KLK4 inhibitor (K i = 0.1 nM) that displayed 100,000-fold selectivity over related KLKs and ...[more]

PMID: 30613336

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Project description:BACKGROUND: Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone. RESULTS: Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity. CONCLUSION: An analog of MCoTI-II is one of the most potent inhibitors of matriptase. SIGNIFICANCE: These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential. 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.

Dataset Information

Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II.

Publications

Potent, Selective, and Cell-Penetrating Inhibitors of Kallikrein-Related Peptidase 4 Based on the Cyclic Peptide MCoTI-II.

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