Biomedical Engineering Reference
In-Depth Information
stability in plasma compared to the original compounds. Despite the fact that
KLK3/PSA can cleave activating peptides when at high concentrations, the
modified peptides exhibited a higher stability.
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9.2.4 Depsipeptides
Depsipeptides are peptides that carry at least one ester linkage in place of
amide.
86
A variety of natural sources produce depsipeptides, including fungi,
bacteria, and various marine organisms. A class of depsipeptides (General
Formula 9.4) isolated from strains of chondromyces bacteria or modified from
the original peptides isolated by simple chemical procedures were found to
specifically inhibit KLK7.
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Compounds 9.5, 9.6, 9.7, and 9.8 have an IC
50
of
1000, 400, 700, and 200 pM, respectively, while they are 410-fold more specific
for KLK7 than for human neutrophile elastase, which is also a chymotrypsin-
like protease. Compounds 9.5, 9.6, and 9.7 were extracted from Chondromyces
crocatus, while compound 9.8 was derived from a chemical reaction of 9.5 with
3-(chloromethyl)-1,5-dimethyl-1H-pyrazole.
Compound 9.5 has been assessed in experimental animals for the treatment
of skin diseases. Specifically, in the mouse skin barrier disruption model
(repeated skin stripping by S-Sqame skin sampling disks), it was found to
accelerate barrier repair by 57%. Also, a single application of a solution of 9.5
in an oxazolone model of allergic contact dermatitis (ACD) in mice resulted in
40% inhibition of inflammatory ear swelling at 10 mM, while at 30 mM, it
caused 46% inhibition of inflammation. Finally, in the 2,4-dinitro-
fluorobenzene (DNFB) model of ACD in swine, two applications of 1%
solution of 9.5 inhibited inflammation by 30% and skin redness by 27%.
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O
O
H
O
NH
N
O
O
OH
N
O
R
8
O
R
3
H
O
O
N
H
O
NH
O
N
H
N
R
5
O
OH
R
2
O
A
1
R
7
H
2
N
O
H
O
X
O
N
R
9
O
H
Y
R
8
=
R
9
=
O
R
6
9.5
9.6
H
H
(H
3
C)
2
HC
9.4
(H
3
CH
2
C)(H
2
C)HC
9.7
H
H
3
C
N
N
9.8
(H
3
C)
2
HC
H
3
C
