Thursday, November 21, 2024
11/21/2024
Currently, more than 55 million people have dementia worldwide and Lewy Body Dementia (LBD) makes up to 30% of all dementia cases. There are no therapies to cure or slow down/stop the progression of LBD, making it a pressing need to develop therapeutics for LBD. The main causal agent in LBD is the aggregation of Alphalpha-synuclein (αS) protein, a neuronal protein that is expressed in neurons. The pathological events in LBD include αS aggregation and the spread of pathogenic αS aggregation via prion-like spread that impairs neuron functions, which leads to LBD phenotypes (cognitive and motor deficits). Therefore, modulation of aggregation and the prion-like spread of αS could be considered a promising therapeutic intervention for LBD. Our lab has synthesized a large library of Oligopyridylamides (OPs) based synthetic protein mimetics with a large chemical diversity. The OPs mimic the topography and side chains of proteins, such as those present at protein aggregation surfaces. We have identified potent OPs that can potently inhibit αS aggregation and LB formation in cellular, neuronal, and C. elegans models. The OP specifically interacts with pathological αS oligomers without displaying any affinity to physiological αS monomers. The OP efficiently crosses the Blood Brain Barrier and inhibits LB formation of LBs in a mouse model without displaying apparent toxicity. Our proposed work is divided into two parts (1) optimization and testing of the pharmaceutical properties of the OPs, (2) testing of OPs to rescue LBD phenotypes in a mouse model. The OPs will be tested for their ADMET properties in human in vitro models. Additionally, based on the chemical structures of OPs, we will design and synthesize OPs to test and optimize the ADMET properties in human in vitro model systems. In tandem, the antagonist activity of the OPs will be tested against αS aggregation in various models. This study will allow the optimization of the pharmaceutical properties of OPs without sacrificing their antagonist activity against pathological LBs. Subsequently, the OP will be tested for their ability to inhibit the LBs in a mouse model. Also, they will be tested to rescue the LBD phenotypes in a mouse model, including the cognitive and motor impairments. The OPs will also be tested for their inherent toxicity in the mouse model via metabolic profiling, where the toxicity of the potential metabolites of OPs will be characterized. Overall, our study will identify potent lead therapeutics for LBD with optimal pharmaceutical and efficacy to rescue LBD phenotypes in the mouse model. In the near future, we expect that the OPs will be ready to be tested for pharmacology, pharmacokinetics, and toxicology assessments in the animal models to further advance them in the clinical trials for LBD.
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