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Literature DB >> 19549601

Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4.

Joakim E Swedberg¹, Laura V Nigon, Janet C Reid, Simon J de Veer, Carina M Walpole, Carson R Stephens, Terry P Walsh, Thomas K Takayama, John D Hooper, Judith A Clements, Ashley M Buckle, Jonathan M Harris.

Abstract

Human kallikrein-related peptidase 4 (KLK4/prostase), a trypsin-like serine protease, is a potential target for prostate cancer treatment because of its proteolytic ability to activate many tumorigenic and metastatic pathways including the protease activated receptors (PARs). Currently there are no KLK4-specific small-molecule inhibitors available for therapeutic development. Here we re-engineer the naturally occurring sunflower trypsin inhibitor to selectively block the proteolytic activity of KLK4 and prevent stimulation of PAR activity in a cell-based system. The re-engineered inhibitor was designed using a combination of molecular modeling and sparse matrix substrate screening.

Entities: Disease Gene Species

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Year: 2009 PMID： 19549601 DOI： 10.1016/j.chembiol.2009.05.008

Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521

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Cited

32 in total

Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4.

Review 1. Circular proteins from plants and fungi.

Review 2. Targeting protein-protein interfaces using macrocyclic peptides.

3. Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor.

4. Albumins and their processing machinery are hijacked for cyclic peptides in sunflower.

Review 5. Using backbone-cyclized Cys-rich polypeptides as molecular scaffolds to target protein-protein interactions.

Review 6. Bile salt hydrolases: Structure and function, substrate preference, and inhibitor development.

7. High-affinity cyclic peptide matriptase inhibitors.

8. An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease.

9. Clinical significance of kallikrein-related peptidase-4 in oral cancer.

10. Associations between smoking and psychiatric comorbidity in U.S. Iraq- and Afghanistan-era veterans.