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

描述（由申请人提供）：阿尔茨海默病（AD）造成了巨大且迅速上升的医疗负担。淀粉样蛋白（Ass）肽起早期致病作用的假说得到了病理学、人类遗传学和生物标志物研究的支持。更具体地说，Ass低聚物引发毒性级联反应，损害突触功能，随后导致进行性认知功能障碍。干预Ass通路的治疗努力主要集中在肽的产生或清除上，到目前为止都令人失望。还需要其他经过验证的AD靶标。在此之前，我们已经研究了Ass寡聚物（aso）对神经元毒性的基础。使用无偏倚的全基因组筛选方法，我们搜索了在大脑中表达的Ass寡聚物特异性结合位点，并鉴定了PrPC。在已报道的aso结合位点中，只有PrPC是通过无偏倚的全基因组筛选确定的。这一发现提出了PrP拮抗剂可能是AD治疗药物的可能性。利用基因敲除和抗prp抗体检测了aso /PrPC复合物对各种临床前AD模型的贡献。已经观察到在缺乏PrPC的情况下会发生某些表型。在其他范式中，PrPC对于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缺陷、突触丧失、5 -羟色胺轴突退化和早期死亡至关重要。关键是，人类AD脑源性提取物需要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拮抗剂作为一类新的AD治疗药物。使用高通量化合物筛选，我们已经确定了几个打击化合物，保护细胞免受砷的有害影响。我们寻求开发这些命中的结构活性关系和药代动力学数据。我们将寻找一个更广泛的化学空间，使用一个专注于纯化的PrPC的n端结构域的分析，该结构域结合人类AD衍生的aso物种。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证据，证明aso与PrPC的相互作用是AD的一个有吸引力的治疗靶点。积极的

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.