%0 Journal Article
%A Palmer, Jonathan
E.
%A Brietske, Breanna M.
%A Bate, Tyler C.
%A Blackwood, Erik A.
%A Garg, Manasa
%A Glembotski, Christopher C.
%A Cooley, Christina B.
%D 2019
%T Reactive
Oxygen Species (ROS)-Activatable Prodrug
for Selective Activation of ATF6 after Ischemia/Reperfusion Injury
%U https://acs.figshare.com/articles/journal_contribution/Reactive_Oxygen_Species_ROS_-Activatable_Prodrug_for_Selective_Activation_of_ATF6_after_Ischemia_Reperfusion_Injury/10269692
%R 10.1021/acsmedchemlett.9b00299.s001
%2 https://acs.figshare.com/ndownloader/files/18548105
%K ER-resident cytochrome P 450 enzymes
%K protein misfolding maladies
%K peroxide-mediated activation
%K ROS-activatable prodrug 1
%K pathway activation
%K ATF 6
%K Selective Activation
%K Reactive Oxygen Species
%K Cyp 1A
%K Biological evaluation
%K molecule ATF 6 activator
%K injury
%K peroxide-mediated toxicity
%K reactive oxygen species
%K target ATF 6 activation
%K Prodrug 1 blocks activity
%X 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.
%I ACS Publications