Substrate-guided Design of a Potent and Selective Kallikrein-related Peptidase Inhibitor for Kallikrein 4

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2009 Jun 25

PMID 19549601

Citations 36

Authors

Joakim E Swedberg

Laura V Nigon

Janet C Reid

Simon J de Veer

Carina M Walpole

Carson R Stephens

Terry P Walsh

Thomas K Takayama

John D Hooper

Judith A Clements

Ashley M Buckle

Jonathan M Harris

Affiliations

Soon will be listed here.

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.

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