Topological Specificity in Inhibitor Recognition by Matrix Metalloproteinases

Alterations in activities of one family of proteases, the metzincins have been implicated
in an array of physiological and pathological processes. In the present study, metzincin
inhibitors were developed by utilizing topologically constrained peptides and
pseudopeptides. The endothelin-family framework was used to develop a disulfideconstrained
topology. This framework was chosen due to its three-dimensional similarity
with a family of endogenous metzincin inhibitors, the tissue inhibitors of
metalloproteases (TIMPs). The collagenous triple-helix was chosen as a second
framework, because only a subset of proteolytic enzymes have the capacity to bind and
hydrolyze a triple-helix. Both templates were successfully modified to generate an array
of inhibitors. These inhibitors displayed subnanomolar to micromolar apparent Ki values,
while being moderately selective metzincin inhibitors. In both cases the threedimensional
structure was determined to be important for activity. This work encourages
the further development of both frameworks as metzincin inhibitors.