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Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury
Version 2 2019-11-20, 22:43
Version 1 2019-11-07, 21:45
journal contribution
posted on 2019-11-20, 22:43 authored by Jonathan
E. Palmer, Breanna M. Brietske, Tyler C. Bate, Erik A. Blackwood, Manasa Garg, Christopher C. Glembotski, Christina B. CooleyWe 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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ER-resident cytochrome P 450 enzymesprotein misfolding maladiesperoxide-mediated activationROS-activatable prodrug 1pathway activationATF 6Selective ActivationReactive Oxygen SpeciesCyp 1ABiological evaluationmolecule ATF 6 activatorinjuryperoxide-mediated toxicityreactive oxygen speciestarget ATF 6 activationProdrug 1 blocks activity
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