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Novel Therapeutics for Treating Neurodegenerative Disorders Based on GSK-3 Inhibitionn 时间:2018-09-29 13:45:43.0

时    间:2018年10月10日 14:00-15:30

    点:医学科学楼B323

    办:IDG/McGovern Institute of Brain Research at Tsinghua University

              School of medicine, Tsinghua university

              XIN Center of Tsinghua University

 

报 告 人:Dr. Hagit Eldar Finkelman (Department of Human Molecular Genetics & Biochemistry

Sackler Faculty of Medicine, Tel Aviv University)

      : Novel Therapeutics for Treating Neurodegenerative Disorders Based on GSK-3 Inhibitionn

摘     要:The serine threonine kinase, glycogen synthase kinase -3 (GSK-3), is recognized as a drug discovery target for treating neurodegenerative disorders. Aberrant activity of GSK-3 provokes deleterious effects in neurons that eventually leads to neuron dysfunction and neuron cell death. Hyperactivity of GSK-3 promotes cellular processes including phosphorylation of tau protein, activation of pro-inflammatory factors, and inhibition of autophagy/lysosomal pathways, all known to contribute to diseases progression. Thus, inhibition of GSK-3 is a promising therapy for treating neurodegeneration.

Many GSK-3 inhibitors have not reached the clinic however, this, in large part due to toxicity and safety issues. Apparently, those GSK-3 inhibitors function as ‘ATP competitive inhibitors’ that often show limited specificity and provoke drug-induced resistance. This is because the ATP binding site is highly conserved among the 500 or so protein kinases.

We suggest that ‘correct’ inhibition of GSK-3 that does not involve the ATP binding element, is a key for a successful clinical use of GSK-3 inhibitors. Accordingly, we design compounds that bind to the unique substrate’s binding site of GSK-3 and function as substrate competitive inhibitors (SCIs). SCIs act as pseudosubstrates or as ‘substrate converted into an inhibitor’, a new inhibition modality that was recently discovered in our laboratory. Our GSK-3 SCI peptides are potent, highly selective, and show ‘good’ pharmacological properties. The GSK-3 SCIs were tested in several in vivo mouse models including models of Alzheimer’s disease, Multiple Sclerosis, Fragile X Syndrome and Huntington’s disease. . Here, I will describe our strategy in developing GSK-3 SCIs and will present the results obtained in the mouse disease models treated with GSK-3 SCIs. I will further discuss our recent approach in discovering new GSK-3 SCI small molecules.

 

报 告 人:Dr. Daniel Segal (School of Molecular Cell Biology & Biotechnology Sagol Interdisciplinary School of Neurosciences, Tel Aviv University)

        : Inhibiting aggregation of amyloidogenic proteins as a strategy for treating neurodegeneration

       要:The hallmark of most neurodegenerative diseases is the assembly of monomers of certain proteins, termed amyloids, into toxic oligomers and fibrils composed of -sheet structures, e.g. A plaques and neurofibrillary tangles of the tau protein in Alzheimer's disease, and α-synuclein in Parkinson's. Since protein self-assembly is an initial key step in the pathology of amyloidosis, intervening in this process can serve both as a prophylactic measure and for therapeutic purposes. I will describe four strategies used in our lab for discovering potential inhibitors of amyloid aggregation and for disassembly of existing amyloid aggregates: (i) Rationally designed small molecules, e.g. Tryptophan-modified naphthoquinones, aimed at interfering with the aromatic π-π interactions during amyloid self-assembly; (ii) High throughput screening of libraries of compounds for such inhibitors (e.g. Palmatine chloride); (iii) Design of peptidomimetics that can specifically bind and inhibit cognate amyloidogenic proteins (e.g. peptide derived from β-synuclein); (iv) Use of natural compounds acting as chemical chaperones (e.g. Mannitol). I will describe results for these approaches using various in vitro assays, cell based assays and in vivo experiments in transgenic animal models of Alzheimer's and Parkinson's. Implications for future pre-clinical studies in humans will be discussed.


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