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

doi:10.1016/j.chembiol.2009.05.008

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › Research › peer-review

103 Citations (Scopus)

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.

Original language	English
Pages (from-to)	633 - 643
Number of pages	11
Journal	Chemistry & Biology
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.chembiol.2009.05.008
Publication status	Published - 2009

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1016/j.chembiol.2009.05.008

Cite this

Swedberg, J. E., Nigon, L. V., Reid, J. C., de Veer, S. J., Walpole, C. M., Stephens, C. R., Walsh, T., Takayama, T. K., Hooper, J. D., Clements, J. A., Buckle, A. M., & Harris, J. M. (2009). Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. Chemistry & Biology, 16(6), 633 - 643. https://doi.org/10.1016/j.chembiol.2009.05.008

@article{3205cf81e3a84892b4604e1cbb0f30e6,

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.",

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

year = "2009",

doi = "10.1016/j.chembiol.2009.05.008",

language = "English",

volume = "16",

pages = "633 -- 643",

journal = "Chemistry \& Biology",

issn = "1074-5521",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4

AU - Swedberg, Joakim E

AU - Nigon, Laura V

AU - Reid, Janet C

AU - de Veer, Simon J

AU - Walpole, Carina M

AU - Stephens, Carson R

AU - Walsh, Terry

AU - Takayama, Thomas K

AU - Hooper, John D

AU - Clements, Judith A

AU - Buckle, Ashley Maurice

AU - Harris, Jonathan M

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19549601

U2 - 10.1016/j.chembiol.2009.05.008

DO - 10.1016/j.chembiol.2009.05.008

M3 - Article

SN - 1074-5521

VL - 16

SP - 633

EP - 643

JO - Chemistry & Biology

JF - Chemistry & Biology

IS - 6

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Cite this