Authors:

Julian B. Novin

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Amyotrophic lateral sclerosis (ALS) poses a significant challenge due to its complexity and limited treatment options. Protein aggregation has been linked to the onset of ALS by inducing cellular stress and disrupting homeostasis. Patients often exhibit a loss in upper and lower motor neurons, leading to progressive weakness in muscles and death by respiratory failure [1]. Hence, the Silverman Group at Northwestern University has made strides in ALS treatment by the identification of cyclohexane 1,3-diones as potential chemicals for treatment. NU-9 has demonstrated promising outcomes by enhancing cellular integrity, reducing protein aggregation levels, and improving motor behavior in preclinical studies. The development of NU-9 (now AKV9) provides increased benefits compared to riluzole [2]. However, further enhancements are necessary to maximize its therapeutic potential. This project focuses on targeted modifications to the structure of NU-9 to improve its efficacy and anti-aggregation capacity. The approach involved retaining critical structural elements of NU-9 while focusing on modifying the chiral oxygen linker. Structures with varying levels of sterically hindering linkers were synthesized, forcing the molecule to adopt stabilized conformations. Initial compounds were tested in cellular models (PC12 cells) with ALS-associated gene mutations, such as SOD-1°**, to evaluate their impact on cellular survival and protein aggregation inhibition. Thus far, it has been observed that the introduction of bulkier, sterically hindered linkers lowers the ability of the molecule to decrease protein aggregation and increase cellular survival. However, the incorporation of a more rigid linker that limited the rotation capacity of the molecule increased the anti-aggregation capacity. Further, it is necessary to determine the molecules' ability to cross the blood-brain barrier and be delivered to the central nervous system (CNS) [3]. Additional molecules that provide potent capacity in the cellular models but have low permeability capability are currently being modified to increase permeability while retaining function.

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Northwestern University

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Co-authors:

Julian B. Novin