Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury
2019-11-20T22:43:26Z (GMT)
by
We describe here the design, synthesis, and biological
evaluation
of a reactive oxygen species (ROS)-activatable prodrug for the selective
delivery of 147, a small molecule ATF6 activator, for
ischemia/reperfusion injury. ROS-activatable prodrug 1 and a negative control unable to release free drug were synthesized
and examined for peroxide-mediated activation. Prodrug 1 blocks activity of 147 by its inability to undergo
metabolic oxidation by ER-resident cytochrome P450 enzymes such as
Cyp1A2, probed directly here for the first time. Biological evaluation
of ROS-activatable prodrug 1 in primary cardiomyocytes
demonstrates protection against peroxide-mediated toxicity and enhances
viability following simulated I/R injury. The ability to selectively
target ATF6 activation under diseased conditions establishes the potential
for localized stress-responsive signaling pathway activation as a
therapeutic approach for I/R injury and related protein misfolding
maladies.
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CC BY-NC 4.0