Design and Synthesis of Novel Targeted Chemical Chaperones as a Basis for Amyotrophic Lateral Sclerosis (ALS) Treatment

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disease characterized by the selective degeneration of motor neurons in the brain and spinal cord, which leads to progressive paralysis and death. ALS is mostly acquired spontaneously (sALS), with inherited disease accounting for only 10-15% of all cases (fALS). Chemical chaperones, which include polyols, trimethyl N-oxide (TMAO), phenylbutyric acid (PBA), and different amino acid derivatives, have been shown to reverse the mislocalization and aggregation of proteins associated with many human diseases. However, using chemical chaperones as drugs is limited by the very high active concentrations (mM range) required for their efficacy. We propose to overcome this obstacle by coupling known chemical chaperones to organelle-targeted moieties, such as lysosomes, ER, Golgi, and mitochondria, where aggregation takes place. Based on this observation, we hypothesize that refolding of Superoxide Dismutase 1 (SOD1) misfolded proteins by chemical chaperones in lysosomes will allow lysosome proteolytic enzymes and proteosome systems to cleave the refolded proteins and prevent SOD1 aggregates and cell death.

In previous study in our research group, we have synthesized several ester- and amide- based TMAO chemical chaperones. The leading compound, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,Ndimethyl propan-1-amine oxide, has displayed both neuronal and astrocyte-protective effects in vitro in a micromolar concentration range, and in daily doses of 10 mg/kg has dramatically improved the neurological functions and has delayed the body weight loss in ALS mice. In addition, the compound significantly increased the survival rate of Drosophila flies. Now, we have synthesized a series of novel compounds using FDA-approved chemical chaperone: phenylbutyric acid (PBA) with different intracellular targeting moieties and linkers. These new compounds might serve as drug candidates for ALS disease treatment.