Biomedical Engineering Reference
In-Depth Information
anti-Klk6 that attenuated disease symptoms.
48
In the same context, adminis-
tration of anti-Klk6 antibodies (i.e. passive immunization) also resulted in the
attenuation of symptoms.
48
9.6 Future Directions
Human KLKs represent a major proteolytic system that participates in many
tissues with additional functions yet to be identified. Despite the fact that KLKs
constitute a relatively new family of serine proteases, certain KLKs were targeted
for therapeutic applications in various disorders mainly in skin diseases such as
NS, psoriasis, etc. and in cancer. Development of animal models will facilitate
the study of KLKs and identification of their as-yet unknown physiological
functions, as well as the assessment of novel pharmaceutical compounds tar-
geting KLKs. Currently, the KLK1
-/-
,
131,132
KLK4
-/-
,
133
and KLK8
-/-
mice
134
have been generated and phenotypically described. KLK1
-/-
displays defects in
calcium renal readsorption
131
and altered renal potassium balance.
135
KLK4
-/-
mice suffered from hypomaturation amelogenesis imperfecta and showed enamel
defects in their teeth,
133
as also observed in humans carrying homozygous KLK4-
inactivating mutations.
136
KLK8
-/-
displayed mild hyperkeratosis with no other
symptoms. Generally, all the aforementioned phenotypes of general KLK
knockout mice are not severe or life-threatening and point to the safety of KLK
targeting. Safety issues in terms of KLK targeting can initially be interrogated in
experimental animal models. In addition, transgenic mice overexpressing
KLK7,
137
KLK6,
21
and KLK5
138
have been studied, as well as double transgenic
KLK2/KLK3 mice to prove activation of KLK3 by KLK2 in vivo, and again
these mice did not shown any adverse effects.
139
The search for new KLK inhibitors is ongoing. Aryl lactones, which were
initially developed as chymotrypsin inhibitors,
140
represent another potential
class of organic inhibitors of KLK proteases. Indeed, the a-aryl lactone 9.32
inhibitedKLK13, indicating that this may provide a new class of lead compounds
for the development of novel inhibitors with high specificity against KLKs.
73
NH
2
H
NH
O
O
9.32
In addition, aptamers may find potential applications as future pharma-
ceutical or and/diagnostic agents, and they may replace antibodies in diagnostic
assays. Recently, an RNA aptamer specific for the active form of KLK3/PSA
