Biomedical Engineering Reference
In-Depth Information
stabilized by the hydroxamate bound to the zinc and the hydroxymethyl-
pyrrolidinyl group embedded into a pocket left to the zinc, at the non-primed
site (Figure 2.8). The different anities between meprin a and b are based on
the structure and amino acid composition of the active site cleft. This cleft
is much narrower in meprin b and additionally surrounded by positively
charged residues (Figure 2.3), which might be more rigid for actinonin-binding.
However, slight modifications of the structure could reveal a highly specific
inhibitor for meprin proteases, the basis for therapeutic agents.
Indeed, in animal models actinonin was demonstrated to suppress athero-
sclerotic plaque formation and to be protective for the renal microcirculation
during sepsis and ischemic acute kidney injury.
73,89,90
The greatest challenge in developing therapeutic inhibitors targeting
proteases is their specificity. For example, the TACE inhibitor Ro32-7315
also interacts with meprin a and b with a K
i
of 1.6 mMand1.6mM,
respectively.
54
There are several other examples of cross-reactivity published
in literature, which may lead to side effects during application.
91
However,
over the last decade, the development of highly specific protease inhibitors
has increased rapidly, thus opening up new possibilities for the treatment of
many diseases.
92-94
Figure 2.8
Binding of actinonin into the active site cleft of human meprins.
Homology models were generated as described Figure 2.3. Actinonin is
displayed in red and bound to the zinc (orange) via the hydroxamate
group indicated by the green lines.
