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Optimization of Pharmacalogic Properties of Molecular Tweezers

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Molecular tweezers (MTs) are compounds that act as Misfolded-Protein Clearance Enhancers (MPCEs) using a unique mechanism. They remodel the self-assembly of amyloidogenic proteins into formation of non-toxic and non-amyloidogenic structures that can be degraded efficiently by the natural clearance mechanisms. A lead MT called CLR01 has been found to prevent the self-assembly of multiple amyloid proteins into toxic oligomers and aggregates, including the proteins involved in Alzheimer’s disease (AD)—amyloid β-protein (Abeta) and tau. Moreover, CLR01 reduced amyloid plaques and neurofibrillary tangles in animal models of AD following subcutaneous administration, demonstrating it was capable of passing through the blood–brain barrier (BBB). With the support of Cure Alzheimer’s Fund, we recently demonstrated that CLR01 had a large safety margin in mice and measured its BBB penetration levels. These levels were found to be 1 to 3 percent. In addition, measurement of oral bioavailability showed that only 1 percent of CLR01 was absorbed through the gastrointestinal system. Therefore, we propose to optimize the oral bioavailability and BBB penetration of CLR01 via formulation and pro-drug approaches.  an important step closer to obtaining FDA approval for initiation of clinical trials.