Trinucleotide repeat disorders include several forms of spinocerebellar ataxia as well as Huntington disease among others. Despite being caused by mutations in different genes, these diseases have at the molecular level a common enabling mechanism that is mediated by a single protein complex called DSIF. These neurodegenerative severe hereditary diseases are progressive and ultimately fatal. DSIF is a prime target for a therapy against such diseases as it has been shown that its function is restricted to enabling the production of only the mutant forms of the different genes. Additionally, the atomic structure of the DSIF protein complex is known, thus making it possible to utilize structure-guided drug design methods to identify potential inhibitors.
The research program includes in addition to the required expertise of the Najmanovich group in structural bioinformatics, structure-guided drug design and molecular biophysics, also complementary collaborations in structural biology and medicinal chemistry to lead to the identification and experimental validation of molecules that inhibit the DSIF complex as a first step in the development of a future therapeutic agent targeting thirteen different diseases. Such a therapy would alleviate the enormous suffering of patients and their families not only in the case Huntington's disease, but also rarer diseases that as such are not targeted by pharmaceutical research and development. Additionally, the research program also includes the continuing development of computational methods applied to drug discovery and their application to additional targets of medical importance.