title: Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4.
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.
authors: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia.
authors: Joakim E
authors: JE
authors: Swedberg
authors: Laura V
authors: LV
authors: Nigon
authors: Janet C
authors: JC
authors: Reid
authors: Simon J
authors: SJ
authors: de Veer
authors: Carina M
authors: CM
authors: Walpole
authors: Carson R
authors: CR
authors: Stephens
authors: Terry P
authors: TP
authors: Walsh
authors: Thomas K
authors: TK
authors: Takayama
authors: John D
authors: JD
authors: Hooper
authors: Judith A
authors: JA
authors: Clements
authors: Ashley M
authors: AM
authors: Buckle
authors: Jonathan M
authors: JM
authors: Harris
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011487:Protein Conformation; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D019151:Peptide Library; D010455:Peptides; D044462:Receptors, Proteinase-Activated; D015842:Serine Proteinase Inhibitors; D007610:Kallikreins; C120801:kallikrein 4