By Jalwa Alfroz
There is currently no available treatment that can promisingly cure the neurodegenerative disorder Huntington’s disease (HD). HD is a progressive neurodegenerative disorder caused by an inherited defect in a single gene encoding the highly conserved protein, Huntington. It is also an autosomal dominant defect, which means that a person only needs one copy of the defective gene to develop the disorder. The expression of the mutant Huntington gene initiates complex pathogenic mechanisms and changes in multiple cellular pathways that result in abnormal protein folding, transcriptional deregulation, and oxidative stress. Although there are speculations as to which mechanisms are affected by the mutant gene, scientists have yet to discover the predominant one. As a result, it complicates the pathology and effective developments of neuro-therapies.
Recently, a major multi-institutional study at the Harvard-affiliated Massachusetts General Hospital, led by Aleksey Kazantasev, identified a novel compound, MIND4, by searching for a scaffold, a group of similar chemical structures, which could act as SIRT2 inhibitors. Kazantasev’s team used derivatives of 8-nitro-5R-quinoline and 5-nitro-8-R-quinoline, substructures of bioactive compounds, as starting templates to screen for different compound activities in acetylation assays with human recombinant SIRT2 protein. Through these in vitro activity tests, the researchers found that MIND4 showed selective concentration-dependent inhibition of human recombinant SIRT2 deacetylase activity. Rat corticostriatal brain slice explants that expressed the mutant Huntington gene were used to demonstrate the protection MIND4 had against the mutant Huntington gene’s neurodegeneration. The team of researchers also found that MIND4 induces the transcriptional activation of the NRF2 pathway in HD and wild-type neuronal cells, which upon activation, regulates the expression of protective antioxidant proteins.
The researchers’ finding that MIND4, SIRT2, and NRF2 activities are independent of each other is a critical step in advancing drug development, indicating that effort to improve the potency of each activity can be carried out separately. MIND4 could be a potential starting template for development of drugs that can target Huntington’s disease and other neurodegenerative diseases.
- Quinti et al., SIRT2- and NRF2-targeting thiazole-containing compound with therapeutic activity in huntington’s disease models. Cell Chemical Biology 23, 849-861 (2016). doi: 10.1016/j.chembiol/2016.05.015
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