Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury

Jonathan E. Palmer, Breanna M. Brietske, Tyler C. Bate, Erik A. Blackwood, Manasa Garg, Christopher C. Glembotski, Christina B. Cooley

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)292-297
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume11
Issue number3
DOIs
StatePublished - Mar 12 2020
Externally publishedYes

Keywords

  • ATF6 activation
  • Cyp1A2
  • ROS-activatable prodrug
  • ischemia-reperfusion injury

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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