Molecular Tweezers

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Summary Researchers at UCLA have developed “molecular tweezers,” which can inhibit folding, assembly, and toxicity of amyloid-β that define Alzheimer’s disease (AD) pathology. In contrast to current therapies which only address symptoms, this therapy directly targets the disease mechanism of AD.   Background Alzheimer’s disease (AD) is an incurable neurodegenerative disease afflicting millions of Americans. Managed care of AD patients presents an enormous financial and social burden on society. Contributing to this burden is the dearth of effective treatments for AD. Current therapies target the symptoms rather than the cause of disease, which involves the deposition of the amyloid-beta (Aβ) and tau proteins into fibrous plaques or tangles in the brain. Aggregation of Aβ and tau proteins is neurotoxic, precipitates neuronal death and impairs cognitive signaling, all of which are characteristic of AD. Therapeutic research efforts in AD continue to focus on the drivers of disease by targeting inhibition of Aβ production, enhancement of Aβ clearance, or disruption of Aβ assembly. Development of therapeutics had previously been hindered by our incomplete understanding of the disease. Recent studies, however, have greatly improved our understanding of the structure and the critical steps involved in the formation of the fibrous plaques. These findings are seeding the development of rationally designed therapies that target specific amino acids of Aβ fibers. Since they specifically target the disease mechanism, such approaches hold great promise for the treatment of AD.   Innovation Researchers at UCLA have developed “Molecular Tweezers,” small molecules that inhibit the assembly of Aβ proteins. Using recent insights to the structure and assembly process of the Aβ protein, specific amino acids critical to fiber formation were identified and targeted in the design of the molecule. These “tweezers” inhibit the assembly and toxicity of Aβ in a non-neurotoxic manner. The invention represents a potential drug for the treatment of AD.   Applications Therapeutic to inhibit progression of the Alzheimer’s Disease. The molecular tweezers and derivatives can be developed for other amyloid-related diseases including Parkinson’s disease, Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease.   Advantages Inhibits the principle cause of AD instead of the symptoms. Disaggregates pre-existing Aβ40 and Aβ42 protein fibrils. The tweezer is non-toxic at concentrations up to 200 μM.   State Of Development The researchers have performed proof-of-concept studies demonstrating the ability of the molecular tweezers to inhibit assembly of Aβ in both in vitro assays and in vivo mouse models. Additional animal studies to further characterize efficacy and pharmacokinetics of the molecule and associated derivatives are underway. In addition, experiments to reveal the structure and mechanism of interaction have been initiated.