Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo

Hiran A Prag; Laura Pala; Duvaraka Kula-Alwar; John F Mulvey; Du Luping; Timothy E Beach; Lee M Booty; Andrew R Hall; Angela Logan; Volha Sauchanka; Stuart T Caldwell; Ellen L Robb; Andrew M James; Zhelong Xu; Kourosh Saeb-Parsy; Richard C Hartley; Michael P Murphy; Thomas Krieg

doi:10.1007/s10557-020-07033-6

Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo

Hiran A Prag, Laura Pala, Duvaraka Kula-Alwar, John F Mulvey, Du Luping, Timothy E Beach, Lee M Booty, Andrew R Hall, Angela Logan, Volha Sauchanka, Stuart T Caldwell, Ellen L Robb, Andrew M James, Zhelong Xu, Kourosh Saeb-Parsy, Richard C Hartley, Michael P Murphy, Thomas Krieg

Pharmacy

Research output: Contribution to journal › Article › peer-review

Abstract

PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters.

METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction.

RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion.

CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.

Original language	English
Pages (from-to)	1-13
Number of pages	13
Journal	Cardiovascular Drugs and Therapy
Volume	36
Issue number	1
DOIs	https://doi.org/10.1007/s10557-020-07033-6
Publication status	Published - 1 Feb 2022

Keywords

Animals
Cardiotonic Agents/chemical synthesis
Cell Line
Disease Models, Animal
Esters/chemistry
Female
Humans
Male
Malonates/chemical synthesis
Mice
Mice, Inbred C57BL
Mitochondria/drug effects
Myocardial Infarction/prevention & control
Myocardial Reperfusion Injury/drug therapy
Prodrugs
Rats
Rats, Wistar
Reactive Oxygen Species/metabolism
Succinic Acid/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10557-020-07033-6

Cite this

Prag, H. A., Pala, L., Kula-Alwar, D., Mulvey, J. F., Luping, D., Beach, T. E., Booty, L. M., Hall, A. R., Logan, A., Sauchanka, V., Caldwell, S. T., Robb, E. L., James, A. M., Xu, Z., Saeb-Parsy, K., Hartley, R. C., Murphy, M. P., & Krieg, T. (2022). Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo. Cardiovascular Drugs and Therapy, 36(1), 1-13. https://doi.org/10.1007/s10557-020-07033-6

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title = "Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo",

abstract = "PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters.METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction.RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion.CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.",

keywords = "Animals, Cardiotonic Agents/chemical synthesis, Cell Line, Disease Models, Animal, Esters/chemistry, Female, Humans, Male, Malonates/chemical synthesis, Mice, Mice, Inbred C57BL, Mitochondria/drug effects, Myocardial Infarction/prevention & control, Myocardial Reperfusion Injury/drug therapy, Prodrugs, Rats, Rats, Wistar, Reactive Oxygen Species/metabolism, Succinic Acid/metabolism",

author = "Prag, {Hiran A} and Laura Pala and Duvaraka Kula-Alwar and Mulvey, {John F} and Du Luping and Beach, {Timothy E} and Booty, {Lee M} and Hall, {Andrew R} and Angela Logan and Volha Sauchanka and Caldwell, {Stuart T} and Robb, {Ellen L} and James, {Andrew M} and Zhelong Xu and Kourosh Saeb-Parsy and Hartley, {Richard C} and Murphy, {Michael P} and Thomas Krieg",

note = "{\textcopyright} 2020. The Author(s).",

year = "2022",

month = feb,

day = "1",

doi = "10.1007/s10557-020-07033-6",

language = "English",

volume = "36",

pages = "1--13",

journal = "Cardiovascular Drugs and Therapy",

issn = "0920-3206",

publisher = "Springer Nature",

number = "1",

}

Prag, HA, Pala, L, Kula-Alwar, D, Mulvey, JF, Luping, D, Beach, TE, Booty, LM, Hall, AR, Logan, A, Sauchanka, V, Caldwell, ST, Robb, EL, James, AM, Xu, Z, Saeb-Parsy, K, Hartley, RC, Murphy, MP & Krieg, T 2022, 'Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo', Cardiovascular Drugs and Therapy, vol. 36, no. 1, pp. 1-13. https://doi.org/10.1007/s10557-020-07033-6

TY - JOUR

T1 - Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo

AU - Prag, Hiran A

AU - Pala, Laura

AU - Kula-Alwar, Duvaraka

AU - Mulvey, John F

AU - Luping, Du

AU - Beach, Timothy E

AU - Booty, Lee M

AU - Hall, Andrew R

AU - Logan, Angela

AU - Sauchanka, Volha

AU - Caldwell, Stuart T

AU - Robb, Ellen L

AU - James, Andrew M

AU - Xu, Zhelong

AU - Saeb-Parsy, Kourosh

AU - Hartley, Richard C

AU - Murphy, Michael P

AU - Krieg, Thomas

PY - 2022/2/1

Y1 - 2022/2/1

N2 - PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters.METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction.RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion.CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.

AB - PURPOSE: Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters.METHODS: We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction.RESULTS: We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion.CONCLUSIONS: The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.

KW - Animals

KW - Cardiotonic Agents/chemical synthesis

KW - Cell Line

KW - Disease Models, Animal

KW - Esters/chemistry

KW - Female

KW - Humans

KW - Male

KW - Malonates/chemical synthesis

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitochondria/drug effects

KW - Myocardial Infarction/prevention & control

KW - Myocardial Reperfusion Injury/drug therapy

KW - Prodrugs

KW - Rats

KW - Rats, Wistar

KW - Reactive Oxygen Species/metabolism

KW - Succinic Acid/metabolism

U2 - 10.1007/s10557-020-07033-6

DO - 10.1007/s10557-020-07033-6

M3 - Article

C2 - 32648168

SN - 0920-3206

VL - 36

SP - 1

EP - 13

JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

IS - 1

ER -

Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo

Abstract

Keywords

UN SDGs

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