Small molecule Beta-sheet breaker peptidemimetics for Alzheimer's therapy

用于治疗阿尔茨海默病的小分子β-折叠肽模拟物

基本信息

批准号：
7459768
负责人：
CLAUDIO SOTO
金额：
$ 16万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7459768
关键词：
APP gene Acute Adverse effects Aftercare Age-Months Alzheimer&apos s Disease Amyloid Amyloid Fibrils Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animal Model Animals Arts Behavior Behavioral Binding Biochemical Biochemistry Biological Biological Assay Biological Availability Blood Blood - brain barrier anatomy Blood capillaries Brain Brain Death Cell Line Cell Membrane Permeability Cell model Cells Cerebrum Characteristics Chemicals Chronic Clinical Clinical Research Coin Computer Simulation Congo Red Coupled Cultured Cells Cutaneous Data Deposition Development Disease Disease Progression Dose Drug Evaluation Drug Kinetics Electron Microscopy Encephalitis End Point Endopeptidases Enzymes Etiology Evaluation Event Failure Figs - dietary Flowcharts Generations Genes Goals Half-Life Histology Human In Vitro Inflammation Inhibitory Concentration 50 Injection of therapeutic agent Intestines Ion Channel Knowledge Lead Liver Extract Measures Memory Memory impairment Modeling Molecular Conformation Mus Nature Neurons Object Attachment Oral Administration Organ Output Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptide Synthesis Peptides Perfusion Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phase II Clinical Trials Principal Investigator Procedures Process Production Property Protein Binding Proteins Reproducibility Research Research Personnel Rodent Route Screening procedure Sedimentation process Senile Plaques Serum Proteins Solubility Solutions Solvents Specificity Standards of Weights and Measures Structure Structure-Activity Relationship Techniques Testing Therapeutic Therapeutic Effect Thioflavin T Tissues Toxic effect Toxicity Tests Toxicology Transgenic Animals Transgenic Mice Transgenic Organisms Tube amyloid fibril formation amyloid formation astrogliosis base beta pleated sheet capillary chemical group chemical stability chemical synthesis concept cytotoxicity design drug development drug discovery evaluation/testing fly healthy volunteer iAbeta5 peptide immunogenicity improved in vitro Assay in vivo information gathering inhibitor/antagonist interest mimetics mouse model mutant neuronal survival neurotoxicity novel peptide A peptide B pharmacophore pre-clinical presenilin-1 prevent programs prophylactic protein folding protein misfolding receptor research clinical testing research study small molecule small molecule libraries synthetic peptide thioflavine uptake

项目摘要

DESCRIPTION (provided by applicant): A hallmark event in Alzheimer's disease (AD) is the misfolding, aggregation and brain deposition of amyloid beta (Abeta) protein in amyloid plaques. Several strategies have been proposed for AD treatment based on inhibiting the amyloid pathway. For the last several years we have been developing short synthetic peptides capable to bind Abeta but unable to become part of a beta-sheet structure (beta-sheet breaker peptides) as novel amyloid inhibitors. We identified a 5-residue peptide (iAbetap) able to inhibit and disassemble amyloid fibrils in vitro, to prevent Abeta neurotoxicity in cell culture, and to arrest and dissolve amyloid plaques in several in vivo animal models. Treatment with iAbeta5p also inhibited neuronal death, brain inflammation and memory impairment in vivo. In addition, the compound showed low toxicity, low immunogenicity, high solubility and reasonably high brain uptake. Based on these results, iAbeta5p is currently under clinical evaluation in humans as a possible treatment for AD. In spite of the good activity in vivo, one of the major weaknesses of this compound is that its peptide nature makes it rapidly degradable and low permeable across biological barriers. The major aim of this project is to use the knowledge accumulated over several years regarding the structure-activity relationship of the lead peptides as well as the tridimensional structure of iAbeta5p to identify non-peptide compounds having a similar structure and activity, but better drug-like properties. The specific aims are the following: 1, to design, synthesize, test and identify in vitro active beta-sheet breaker peptidemimetics. To reach this aim we will follow two parallel approaches: highthroughput screening of existing compounds having the relevant pharmacophore groups and rational design and synthesis of novel chemical compounds that mimic the structure of the lead beta-sheet breaker peptide; 2, characterization of newly identified small molecule beta-sheet breakers for pharmacological properties, including stability, bioavailability, brain uptake, selectivity and preliminary toxicology. 3, improve potency and drug-like properties of hit compounds by medicinal chemistry; 4, detailed study of the in vivo activity of selected compounds using transgenic mice models of AD. The findings obtained in this project should lead to the generation of second generation non-peptide beta-sheet breakers with improved drug-like properties, which will offer a great promise for the efficient treatment of AD.

描述（由申请人提供）：阿尔茨海默氏病（AD）中的标志性事件是淀粉样蛋白在淀粉样蛋白斑块中淀粉样蛋白（ABETA）蛋白的错误折叠，聚集和脑沉积。已经提出了基于抑制淀粉样蛋白途径的AD治疗的几种策略。在过去的几年中，我们一直在开发能够结合ABETA但无法成为新型淀粉样蛋白抑制剂的β-片结构（β-片断裂肽）的一部分的短合成肽。我们鉴定了一个5-残基肽（Iabetap）能够在体外抑制和拆卸淀粉样蛋白原纤维，以防止细胞培养中的Abeta神经毒性，并在几种体内动物模型中停止和溶解淀粉样蛋白斑。 Iabeta5p治疗还抑制了体内神经元死亡，脑部炎症和记忆力障碍。此外，该化合物的毒性低，免疫原性，高溶解度和相当高的脑摄取。基于这些结果，IABETA5P目前正在人类的临床评估中，作为AD的可能治疗方法。尽管体内活性良好，但该化合物的主要弱点之一是其肽性质使其在生物屏障中迅速降解且渗透性低。该项目的主要目的是利用几年来积累的有关铅肽的结构活性关系以及IABETA5P的三维结构来识别具有相似结构和活性的非肽化合物，但类似药物样的特性。具体目的是：1，设计，合成，测试和识别体外活性β-折叠式断裂器肽仪。为了达到这一目标，我们将遵循两种平行的方法：对具有相关药效基团的现有化合物的高通量筛选，以及合理的设计以及新型化学化合物的合成，这些化合物模仿了铅β-片断路器肽的结构； 2，新鉴定的针对药理特性的小分子β-β-断路器的表征，包括稳定性，生物利用度，脑吸收，选择性和初步毒理学。 3，通过药物化学改善命中化合物的效力和类似药物样特性； 4，使用AD的转基因小鼠模型对所选化合物的体内活性的详细研究。该项目中获得的发现应导致具有改善类似药物的特性的第二代非肽betaβ断裂器的产生，这将为AD有效治疗提供巨大的希望。