Targeting A-beta with evolved site-specific proteases

使用进化的位点特异性蛋白酶靶向 A-β

基本信息

  • 批准号:
    7361795
  • 负责人:
  • 金额:
    $ 16.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-03-01 至 2010-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In this proposal we plan to develop therapeutic protease agents designed to target the presumed underlying pathogenic mechanism in Alzheimer's disease (AD) - accumulation of amyloid-beta (Ab) peptide - which proved to be a difficult target for small-molecule strategies. Specifically, we wish to exploit a selection-based directed evolution scheme for rapid identification of proteases with high selectivities and catalytic activities against a specific peptide fragment within Ab. Recent evidence suggests that the formation of amyloid fibrils, as well as the cytotoxic soluble aggregates is an equilibrium-controlled process, triggered by accumulation of Ab. Moreover, defects in both biogenesis and clearance mechanisms of Ab have been linked to the pathogenicity of AD. We hypothesize, therefore, that our catalytic agents will be able to rescue the Ab clearance pathway by exhibiting an internally amplifiable activity against the amyloidogenic peptide. Specifically, we expect that the cleavage of monomoric Ab will be able to 1) shift the aggregation equilibrium toward less complex species and 2) generate potent aggregation inhibitors in situ in the form of proteolysis products. We believe, therefore, that the site-selective proteolysis of Ab presents a unique opportunity for the development of a highly effective therapeutic strategy against this debilitating disease and we plan to accomplish the following Specific Aims in developing this approach: Specific Aim 1: Using a site-specific protease as a starting scaffold, we plan to develop a genetic selection system capable of identifying uniquely active species with nonnative activities against Ab from a vast collection of genetically encoded sequence permutations. Specific Aim 2: We will confirm anti-Ab activities of the evolved proteases using an authentic amyloidogenic substrate and further characterize these agents, using 1) kinetic analysis for the substrate specificity analysis, 2) biphasic assays for assessment of their deaggregation properties, and 3) cell viability assay for the measure of their cytoprotective propensity. Specific Aim 3: Finally, we will optimize the pharmacokinetic properties of the anti-Ab proteases by improving their stability to systemic metabolism and reducing their immonogenicity. The expected outcome of this research will be identification of therapeutic proteolytic agents capable of attacking putative AD pathogens through catalytic degradation of the Ab monomers into non-fibrinogenic and, potentially, anti-amyloid fragments. Our long-term goal is to develop therapeutic strategies, targeting the underlying pathogenic mechanisms in AD.
描述(由申请人提供):在本提案中,我们计划开发治疗性蛋白酶制剂,旨在针对阿尔茨海默病(AD)中假定的潜在致病机制-淀粉样蛋白- β (Ab)肽的积累-这被证明是小分子策略的困难靶点。具体来说,我们希望开发一种基于选择的定向进化方案,用于快速鉴定具有高选择性和对Ab内特定肽片段催化活性的蛋白酶。最近的证据表明,淀粉样蛋白原纤维的形成以及细胞毒性可溶性聚集体是一个平衡控制的过程,由Ab的积累触发。Ab的生物发生和清除机制的缺陷与AD的致病性有关。因此,我们假设,我们的催化剂将能够通过展示一种内部可扩增的抗淀粉样蛋白肽的活性来挽救Ab清除途径。具体来说,我们预计单单体Ab的裂解将能够1)将聚集平衡转移到不太复杂的物种上,2)以蛋白水解产物的形式在原位产生有效的聚集抑制剂。因此,我们相信,Ab的位点选择性蛋白水解为开发针对这种使人衰弱的疾病的高效治疗策略提供了一个独特的机会,我们计划在开发这种方法时实现以下具体目标:

项目成果

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Sergey N. Savinov其他文献

Sergey N. Savinov的其他文献

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{{ truncateString('Sergey N. Savinov', 18)}}的其他基金

Rescuing the anti-HIV activity of APOBEC3G with small-molecule chaperons
用小分子伴侣挽救 APOBEC3G 的抗 HIV 活性
  • 批准号:
    7858536
  • 财政年份:
    2009
  • 资助金额:
    $ 16.2万
  • 项目类别:
Rescuing the anti-HIV activity of APOBEC3G with small-molecule chaperons
用小分子伴侣挽救 APOBEC3G 的抗 HIV 活性
  • 批准号:
    7419495
  • 财政年份:
    2009
  • 资助金额:
    $ 16.2万
  • 项目类别:
Targeting A-beta with evolved site-specific proteases
使用进化的位点特异性蛋白酶靶向 A-β
  • 批准号:
    7565916
  • 财政年份:
    2008
  • 资助金额:
    $ 16.2万
  • 项目类别:

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