Discovery of bioactive small-molecule inhibitor of poly adp-ribose polymerase: implications for energy-deficient cells.
Poly (ADP-ribose) polymerase (PARP1) is a nuclear protein that, when overactivated by oxidative stress-induced DNA damage, ADP ribosylates target proteins leading to dramatic cellular ATP depletion. We have discovered a biologically active small-molecule inhibitor of PARP1. The discovered compound inhibited PARP1 enzymatic activity in vitro and prevented ATP loss and cell death in a surrogate model of oxidative stress in vivo. We also investigated a new use for PARP1 inhibitors in energy-deficient cells by using Huntington's disease as a model. Our results showed that insult with the oxidant hydrogen peroxide depleted cellular ATP in mutant cells below the threshold of viability. The protective role of PARP1 inhibitors against oxidative stress has been shown in this model system.
Altmann
Stephen M
SM
Massachusetts General Institute for Neurodegenerative Disease and Harvard Medical School, Department of Neurology, Massachusetts General Hospital, Charlestown, 02129, USA.
Muryshev
Andrey
A
Fossale
Elisa
E
Maxwell
Michele M
MM
Norflus
Francine N
FN
Fox
Jonathan
J
Hersch
Steven M
SM
Young
Anne B
AB
MacDonald
Marcy E
ME
Abagyan
Ruben
R
Kazantsev
Aleksey G
AG
D000255:Adenosine Triphosphate / Q000378:metabolism; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000255:Adenosine Triphosphate