Hydrogen Peroxide Activated Matrix Metalloproteinase Inhibitors: A Prodrug Approach

摘要

Matrix metalloproteinases (MMPs) are a family of structurally related Zn~(II)-dependent hydrolytic enzymes involved in the breakdown of the extracellular matrix. MMPs are secreted as zymogens, and are activated by cleavage of the propeptide domain by proteases, other MMPs, or by reactive oxygen species (ROS). In particular, the activation of MMPs by ROS during ischemia-induced inflammatory response leads to the breakdown of the blood-brain barrier (BBB) resulting in edema and cell death. The strong correlation between ROS-activation of MMPs and the disruption of the BBB has led to several studies on the use of MMP inhibitors (MMPi) as therapeutics for treating reperfusion injury associated with stroke. Inhibition of MMPs after stroke with a variety of broad-spectrum MMPi have shown that MMP inhibition greatly reduced ischemic brain injury. While the use of MMPi to reduce the effects of BBB disruption following stroke has been clearly established, the major challenge for MMPi in this area is the need for temporal and spatial control of their inhibitory activity.