Small Molecule Development of PrPc Antagonists for the Treatment of Alzheimer's D

描述(由申请者提供)：阿尔茨海默病(AD)造成了巨大的、迅速上升的医疗负担。病理、人类遗传学和生物标记物研究支持了淀粉样β蛋白(Ass)多肽起早期致病作用的假说。更具体地说，Ass寡聚体会引发毒性级联反应，损害突触功能，随后导致进行性认知功能障碍。干预Ass途径的治疗努力主要集中在多肽的产生或清除上，到目前为止一直令人失望。还需要AD的其他经过验证的目标。在此之前，我们已经研究了Ass寡聚体(ASSO)对神经元的毒性基础。采用全基因组无偏筛选的方法，寻找脑内表达的Ass寡聚体特异性结合位点，鉴定出PrPC。在已报道的Asso结合位点中，只有PrPC是通过无偏见的全基因组筛选鉴定出来的。这一发现增加了PrP拮抗剂可能是AD疗法的可能性。利用基因敲除和抗PrP抗体研究了Asso/PrPC复合体在各种临床前AD模型中的作用。已观察到某些表型在没有PrPC的情况下发生。在其他模式中，PrPC在Asso诱导的细胞死亡和突触可塑性受损以及AD转基因诱导的空间记忆障碍、突触丢失、5-羟色胺轴突变性和早期死亡中是必不可少的。关键是，人类AD脑提取液需要PrPC来抑制突触可塑性。令人鼓舞的是，用抗PrPC抗体治疗老年记忆受损的APP/PS1小鼠可以逆转记忆缺陷。我们寻求开发PrPC拮抗剂作为治疗AD的一类新药物。利用高通量化合物筛选，我们已经鉴定了几种命中化合物，它们可以保护细胞免受Asso的有害影响。我们寻求开发这些药物的结构活性关系和药代动力学数据。我们将使用一种专注于PrPC纯化的N末端结构域的实验来搜索更广泛的化学空间，PrPC与人AD衍生的Asso物种结合。对于选定的PrP拮抗剂化合物，我们将在小鼠身上测试临床前治疗效果。这些实验有可能提供临床前的概念证据，证明Asso与PrPC的相互作用是治疗AD的一个有吸引力的靶点。正性 结果将证明进一步的先导化合物优化和毒理学研究为临床开发做准备。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) extracts a massive and rapidly rising health care burden. The hypothesis that the Amyloid beta (Ass) peptide plays an early causative role is supported by pathology, by human genetics and by biomarker studies. More specifically, Ass oligomers trigger a toxic cascade that impairs synaptic function and subsequently leads to progressive cognitive dysfunction. Therapeutic efforts to intervene in the Ass pathway have focused on the production or clearance of the peptide, and have been disappointing so far. Additional validated targets for AD are needed. Previously, we have studied the basis for Ass oligomer (Asso) toxicity for neurons. Using an unbiased genome- wide screening method we searched for Ass oligomer-specific binding sites expressed in brain, and identified PrPC. Amongst reported Asso binding sites, only PrPC was identified through an unbiased, genome-wide screen. This finding raises the possibility that PrP antagonists might be AD therapeutics. The contribution of Asso/PrPC complexes to various preclinical AD models has been examined using gene knockout and anti-PrP antibodies. Certain phenotypes have been observed to occur in the absence of PrPC. In other paradigms, PrPC is essential for Asso-induced cell death and impaired synaptic plasticity, as well as AD transgene-induced spatial memory deficits, synapse loss, serotonin axon degeneration and early death. Critically, human AD brain-derived extracts require PrPC to suppress synaptic plasticity. Encouragingly, the treatment of aged, memory-impaired APP/PS1 mice with anti-PrPC antibody reverses memory deficits. We seek to develop PrPC antagonists as a novel class for AD therapy. Using high throughput chemical compound screening we have identified several hit compounds, which protect cells from the detrimental effects of Asso. We seek to develop structural activity relationships and pharmacokinetic data for these hits. We will search a broader chemical space using an assay focused on the purified N-terminal domain of PrPC which binds human AD derived Asso species. For selected PrP antagonist compounds, we will test preclinical therapeutic efficacy in mice. These experiments have the potential to provide preclinical proof of concept that the interaction of Asso with PrPC is an attractive therapeutic target for AD. Positive outcomes will justify further lead compound optimization and toxicology studies in preparation for clinical development.