TY - JOUR
T1 - Reactive Oxygen Species (ROS)-Activatable Prodrug for Selective Activation of ATF6 after Ischemia/Reperfusion Injury
AU - Palmer, Jonathan E.
AU - Brietske, Breanna M.
AU - Bate, Tyler C.
AU - Blackwood, Erik A.
AU - Garg, Manasa
AU - Glembotski, Christopher C.
AU - Cooley, Christina B.
N1 - Funding Information:
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. This work was supported by the Welch Foundation (W-1984-20190330 and W-0031), the American Chemical Society Petroleum Research Fund (57370-UNI7), the National Science Foundation (CHE-1726441), the Arnold and Mabel Beckman Foundation, the San Antonio Area Foundation, and Trinity University. E.A.B. was supported by the American Heart Association (17PRE33670796), the National Institutes of Health (1F31HL140850), the Rees-Stealy Research Foundation, San Diego State University (SDSU) Heart Institute, the Inamori Foundation, and the ARCS Foundation, Inc., San Diego Chapter. C.C.G. was supported by National Institutes of Health grants R01 HL135893, R01 HL75573, and R01 HL104535. The authors declare no competing financial interest.
Funding Information:
This work was supported by the Welch Foundation (W-1984-20190330 and W-0031), the American Chemical Society Petroleum Research Fund (57370-UNI7), the National Science Foundation (CHE-1726441), the Arnold and Mabel Beckman Foundation, the San Antonio Area Foundation, and Trinity University. E.A.B. was supported by the American Heart Association (17PRE33670796) the National Institutes of Health (1F31HL140850), the Rees-Stealy Research Foundation, San Diego State University (SDSU) Heart Institute the Inamori Foundation, and the ARCS Foundation, Inc., San Diego Chapter. C.C.G. was supported by National Institutes of Health grants R01 HL135893 R01 HL75573, and R01 HL104535.
Funding Information:
Acknowledgment is made to the Welch Foundation, National Science Foundation, National Institutes of Health, Arnold and Mabel Beckman Foundation, San Antonio Area Foundation, and Trinity University. We further acknowledge the Donors of the American Chemical Society Petroleum Research Fund for support of this research. We would also like to thank Dr. William Ellison for helpful discussions regarding statistical analysis.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/3/12
Y1 - 2020/3/12
N2 - 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.
AB - 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.
KW - ATF6 activation
KW - Cyp1A2
KW - ROS-activatable prodrug
KW - ischemia-reperfusion injury
UR - http://www.scopus.com/inward/record.url?scp=85074748037&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074748037&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.9b00299
DO - 10.1021/acsmedchemlett.9b00299
M3 - Article
AN - SCOPUS:85074748037
VL - 11
SP - 292
EP - 297
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 3
ER -