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Abstract
<p class="first" id="d483318e160">
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<img alt="" class="figure" src="/document_file/588453aa-7e8a-42f2-b161-45faba5c110c/PubMedCentral/image/ml-2018-00422h_0006"/>
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</p><p id="d483318e164">Kallikrein-related
peptidase 4 (KLK4) is a serine protease that
has putative intracellular and extracellular functions in prostate
cancer progression. Here we show that MCoTI-II, a 34-amino acid cyclic
peptide found in the seeds of red gac (
<i>Momordica cochinchinensis</i>), is an inhibitor of KLK4. By grafting a preferred
KLK4 cleavage
sequence into MCoTI-II, we produced a highly potent KLK4 inhibitor
(
<i>K</i>
<sub>i</sub> = 0.1 nM) that displayed 100,000-fold
selectivity over related KLKs and the ability to penetrate cells.
Additionally, by substituting positively charged noncontact residues
in this compound, we produced a potent and selective KLK4 inhibitor
that does not penetrate cells. The inhibitors were shown to be nontoxic
to human cells and stable in human serum. These KLK4 inhibitors provide
useful chemical tools to further define the role(s) of both intracellular
and extracellular KLK4 in prostate cancer cell lines and disease models.
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