Biomedical Engineering Reference
In-Depth Information
inflammation in lung bronchial cells by releasing TGFa (transforming growth
factor a) from the cell surface.
38
Interestingly, these workers found an increased
expression of meprin in mice suffering from cystic fibrosis, compared to healthy
animals. Hence, meprin proteases may represent promising targets in the
development of pathological conditions characterized by the excess of fibrous
connective tissue.
2.3 Inhibitors of Meprin a and b
The regulation of proteolytic activity is a promising approach for the treatment
of diseases such as cancer, cardiovascular diseases, Alzheimer's disease, and
AIDS.
In vivo, proteolytic activity can be regulated at the expression level by specific
activators or endogenous inhibitors. The tissue inhibitors of metalloproteinases
(TIMPs) are well characterized as potent inhibitors for MMPs and ADAMs,
but not astacins, involved in cancer progression and cardiovascular diseases.
86
Recently, fetuin-A and cystatin C were identified as endogenous inhibitors
for meprins.
87
Fetuin-A is a negative acute phase protein involved in inflam-
matory diseases, thus being a potential physiological regulator of meprin
activity, with a K
i
of 4.2
10
5
M for meprin a and a K
i
of 1.1
10
6
M for
meprin b. However, the inhibition of meprin a by fetuin was 40 times weaker
than that of meprin b, hence probably not in a physiological range. It emerged
that cystatin C, which contains domains homologous to fetuin-A, was an
inhibitor for human meprin a (K
i
¼
8.5
10
6
M), but interestingly not for
meprin b.
Regardless of this, endogenous inhibitors are mostly not appropriate for use
as therapeutics, owing to their broad specificity. Hence, smaller non-peptidic
molecules, isolated from natural sources or produced by chemically synthesis,
may act more specifically.
Synthetic metalloprotease inhibitors often target the catalytic zinc ion to
prevent the enzyme from hydrolyzing a peptide bond.
88
These compounds
can act through a hydroxamate group, chelating the metal within the active
site cleft.
Human meprins are inhibited by hydroxamic acid derivatives such as
batimastat, galardin, and Pro-Leu-Gly-hydroxamate, by TAPI-0 (tumor
necrosis factor a protease inhibitor-0) and TAPI-2, and by thiol-based
compounds such as captopril (Figure 2.7).
54
Possible therapeutic targets of
these inhibitors are the MMPs (matrix metalloproteases), TACE (tumor
necrosis factor a-converting enzyme or ADAM17), and ACE (angiotensin-
converting enzyme).
The most effective inhibitor of meprin a and b is the naturally occurring
hydroxamate actinonin (inhibition constant K
i
¼
20 nM and 2 mM, respec-
tively). Although certain MMPs are also sensitive to this molecule, the differ-
ence in the K
i
is significant, thus being an appropriate tool to control meprin
activity. Actinonin fits well
into the active site cleft of human meprins,
