Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4.
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.
Swedberg
Joakim E
JE
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia.
Nigon
Laura V
LV
Reid
Janet C
JC
de Veer
Simon J
SJ
Walpole
Carina M
CM
Stephens
Carson R
CR
Walsh
Terry P
TP
Takayama
Thomas K
TK
Hooper
John D
JD
Clements
Judith A
JA
Buckle
Ashley M
AM
Harris
Jonathan M
JM
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
D019151:Peptide Library; D010455:Peptides; D044462:Receptors, Proteinase-Activated; D015842:Serine Proteinase Inhibitors; D007610:Kallikreins; C120801:kallikrein 4