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

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

Research output: Contribution to journalArticleResearchpeer-review

94 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)633 - 643
Number of pages11
JournalChemistry and Biology
Issue number6
Publication statusPublished - 2009

Cite this