A novel class of cardioprotective small-molecule PTP inhibitors

Salvatore Antonucci, Moises Di Sante, Justina Sileikyte, Jordan Deveraux, Tyler Bauer, Michael J. Bround, Roberta Menabò, Melanie Paillard, Petra Alanova, Michela Carraro, Michel Ovize, Jeffery D. Molkentin, Michael Cohen, Michael A. Forte, Paolo Bernardi, Fabio Di Lisa, Elizabeth Murphy

Research output: Contribution to journalArticle

Abstract

Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.

Original languageEnglish (US)
Article number104548
JournalPharmacological Research
Volume151
DOIs
StatePublished - Jan 2020

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Permeability
Muscle Cells
Cyclosporine
Reperfusion Injury
Mitochondria
Cardiotonic Agents
Cardiac Myocytes
Reactive Oxygen Species
Cell Death
cyclophilin D
Wounds and Injuries
Pharmaceutical Preparations

Keywords

  • Caffeine (PubChem CID: 2519)
  • Calcimycin (PubChem CID: 40486)
  • Cardiomyocytes
  • Cardioprotection
  • Compound 63 (PubChem CID: 75204518)
  • Cyclosporine A (PubChem CID: 5284373)
  • Ischemia
  • Mitochondria
  • MitoParaquat (PubChem CID: 129909777)
  • Permeability transition
  • Reperfusion

ASJC Scopus subject areas

  • Pharmacology

Cite this

Antonucci, S., Di Sante, M., Sileikyte, J., Deveraux, J., Bauer, T., Bround, M. J., ... Murphy, E. (2020). A novel class of cardioprotective small-molecule PTP inhibitors. Pharmacological Research, 151, [104548]. https://doi.org/10.1016/j.phrs.2019.104548

A novel class of cardioprotective small-molecule PTP inhibitors. / Antonucci, Salvatore; Di Sante, Moises; Sileikyte, Justina; Deveraux, Jordan; Bauer, Tyler; Bround, Michael J.; Menabò, Roberta; Paillard, Melanie; Alanova, Petra; Carraro, Michela; Ovize, Michel; Molkentin, Jeffery D.; Cohen, Michael; Forte, Michael A.; Bernardi, Paolo; Di Lisa, Fabio; Murphy, Elizabeth.

In: Pharmacological Research, Vol. 151, 104548, 01.2020.

Research output: Contribution to journalArticle

Antonucci, S, Di Sante, M, Sileikyte, J, Deveraux, J, Bauer, T, Bround, MJ, Menabò, R, Paillard, M, Alanova, P, Carraro, M, Ovize, M, Molkentin, JD, Cohen, M, Forte, MA, Bernardi, P, Di Lisa, F & Murphy, E 2020, 'A novel class of cardioprotective small-molecule PTP inhibitors', Pharmacological Research, vol. 151, 104548. https://doi.org/10.1016/j.phrs.2019.104548
Antonucci S, Di Sante M, Sileikyte J, Deveraux J, Bauer T, Bround MJ et al. A novel class of cardioprotective small-molecule PTP inhibitors. Pharmacological Research. 2020 Jan;151. 104548. https://doi.org/10.1016/j.phrs.2019.104548
Antonucci, Salvatore ; Di Sante, Moises ; Sileikyte, Justina ; Deveraux, Jordan ; Bauer, Tyler ; Bround, Michael J. ; Menabò, Roberta ; Paillard, Melanie ; Alanova, Petra ; Carraro, Michela ; Ovize, Michel ; Molkentin, Jeffery D. ; Cohen, Michael ; Forte, Michael A. ; Bernardi, Paolo ; Di Lisa, Fabio ; Murphy, Elizabeth. / A novel class of cardioprotective small-molecule PTP inhibitors. In: Pharmacological Research. 2020 ; Vol. 151.
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abstract = "Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.",
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KW - Reperfusion

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