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Targeting PARP1 Is Effective In Protecting HD Cells from Damage

According to a study conducted by the researchers at the MassGeneral Institute for Neurodegenerative Disease (MIND) it was found that inhibitor of an enzyme known as Poly //(ADP-ribose) polymerase (PARP1) is very effective in protecting Huntington’s disease affected cells from undergoing damage.

By targeting this enzyme new drugs can be developed to treat Huntington's disease (HD) and other disorders characterized by low cellular energy levels. The study results are published in the journal of Chemistry & Biology. ‘While PARP1 is essential for the repair of damaged DNA, we also know that, if overactivated, it can cause cell death by excessive energy depletion,’ says Aleksey Kazantsev, PhD, director of the MIND High Throughput Drug Screening Laboratory, who led the current study. ‘It has recently been shown that neurons from patients with Huntington's appear to be energy-deficient, so we hypothesized that modest stresses that would be tolerated by healthy cells could send HD cells below a viable energy threshold and that blocking PARP1 activation could be protective.’

To test this hypothesis the MIND researchers first ran a computer search of their small-molecule library for potential novel inhibitors of PARP1, searching for those with structural similarities to known inhibitors. ‘Safety and efficacy of human drugs depends on many factors, so it's hard to predict which inhibitor would be most effective against a specific disorder. The more diverse novel inhibitors can be identified, the more chances there are of developing safe and effective drugs,’ Kazantsev explains.

Two candidate molecules were identified as potential PARP1 inhibitors based on their structure, and both of them were confirmed to inhibit the enzyme's activity in an in vitro assay. However, when tested using cultured human and rat cells, only one of the candidate molecules, K245-14, successfully prevented the death of cells in which PARP1 had been overactivated. The nex
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