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