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bioactive peptide bradykinin from high-molecular-weight kininogen (HMWK)
(Figure 9.1B). 5 Tissue kallikreins, renamed tissue kallikrein-related peptidases
(KLKs), according to the most recent international nomenclature, 6 constitute
the largest family of serine proteases in the human genome and are tandemly
arranged on human chromosome 19q13.4. 7 All KLK genes encode for serine
proteases with trypsin-, chymotrypsin-like, or mixed activity. KLK1, also
referred to as tissue kallikrein, releases Lys-bradykinin from low-molecular-
weight kininogen (LMWK) (Figure 9.1B). Human KLKs act alone or in
complex proteolytic cascades named the 'KLK activome.' KLK cascades act in
a tissue-specific manner and were implicated in various (patho)physiological
processes, 8-12 as summarized below.
9.1.2 Why Should We Target KLKs? Association of KLK with
In recent years, a number of proteases have been selected as molecular targets
for drug design and development, and several eventually entered the pharma-
ceutical market. Inhibitors of the following are widely known: (a) ACE
metalloprotease (e.g. captopril, enalapril), (b) thrombin serine protease (e.g.
argatroban), (c) HIV aspartic protease (e.g. ritonavir), the proteasome inhi-
bitor bortezomib, and many more. 13 In December 2009, ecallantide—a drug
that targets plasma kallikrein—received FDA approval for acute attacks of
hereditary angioedema. 14 Ecallantide is a 60-amino-acid residue recombinant
peptide produced in Pichia pastoris that was identified and isolated by phage
display. Ecallantide acts as a reversible high-anity inhibitor of plasma kal-
likrein with a K i of 44 pM. 15
On the other hand, expression of specific KLKs has been associated with
diverse physiological functions (i.e. semen liquefaction, activation of anti-
microbial peptides), and their aberrant regulation has been implicated in
common human diseases, including hypertension, renal dysfunction, skin dis-
eases, inflammation, allergies, neurodegeneration, and cancer. 7,8,11,16,17
Therefore, KLK targeting is expected to provide new pharmaceutical com-
pounds for the treatment of these pathologies. Cancer
In addition to KLK3/PSA, which has found clinical applications in the diag-
nosis and monitoring of prostate cancer, 18 several other KLKs are considered
potential biomarkers, as they show deregulated expression in various types of
cancer. 19 The potential functions of KLKs in cancer growth and progression
are currently under investigation. Certain KLKs have been shown to cleave
components of the extracellular matrix in vitro, so they may promote cancer
invasion and metastasis. 7,16 A number of studies have implicated KLKs in the
induction of epithelial-to-mesenchymal transition (EMT), which is a critical
step in cancer metastasis. In prostate cancer, expression of KLK3 and KLK4
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