DNA damage from radiation therapy, chemotherapy, or oxidative stress kicks the enzyme Poly(ADP-Ribose) Polymerase (PARP) into overdrive. Although PARP is useful for repairing DNA in the nucleus, it can also deplete cellular NAD+ and ATP from mitochondria, ultimately leading to dysfunction and necrotic cell death. Several neurological disorders such as traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), and neurodegenerative diseases are associated with PARP overactivity and NAD+ depletion. General inhibition of PARP offers metabolic protection, but it does so at the expense of DNA repair in the nucleus, which can itself lead to cell death. We present a new compound that inhibits PARP activity specifically in the mitochondria to reduce the harmful effects of environmental stress and stave off cell death.
Description
To hone in on mitochondrial PARP, we added a targeting sequence to the PARP-inhibitor veliparib, which is currently in multiple late-stage clinical trials for cancer, to create mitoparib. Whereas veliparib fights cancer by hastening DNA damage to invoke cell death, mitoparib protects environmentally-stressed cells against cell death by inhibiting PARP-related NAD+ depletion in the mitochondria while permitting homeostatic PARP-related DNA repair in the nucleus. Experiments with oxygen- and glucose-deprived rat neurons demonstrate that mitoparib reduces mitochondrial PARP activity and ameliorates mitochondrial swelling associated with necrosis. In mouse embryos, mitoparib decreases radiation-induced cell death. Mitoparib presents an exciting solution to targeting mitochondrial PARP activity and prevent cell death.
Applications
· Preventing oxidative stress-induced necrosis caused by radiation or chemotherapy during cancer treatment
· Treating neurological disorders, i.e. Parkinson’s, Alzheimer’s, TBI, and CTE
· Treating ischemia-reperfusion injury, such as occurs during organ transplantation
· Treating overwhelming infection
· Treating other disorders involving mitochondrial dysfunction
Advantages
· Concentrates in mitochondria
· Preserves NAD+ in mitochondria
· Does not interfere with DNA repair in the nucleus
· Effective at low doses
· Could be used in tandem with DNA-damaging cancer treatments
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/US11759524B2
