Novel Approaches for Tau PROTAC Drug Discovery

Tau PROTAC药物发现的新方法 阿尔茨海默病(AD)、额颞叶痴呆(FTD)、进行性核上性麻痹(PSP)是一组 以过度磷酸化tau(P-tau)病理性堆积为特征的神经退行性疾病 以细胞内成对螺旋细丝(PHF)或神经原纤维缠结(NFT)或聚集体的形式存在的蛋白质， 在受影响的大脑区域的神经元和神经胶质细胞内，导致细胞死亡。移除集合体的几种方法 致病性tau的研究都失败了，包括抗体疗法。去除聚集蛋白质的新方法是 想要。针对嵌合体的蛋白水解靶向降解(PROTACs)已成为一种新的研究方向 治疗方式。PROTAC是一种同时与靶结合的异质双功能小分子 蛋白质和泛素E3连接酶，从而导致泛素化和随后的靶标降解。 它们提供了一种新的机会，以一种独立于酶或信号活性的方式调节蛋白质。 PROTAC药物具有许多优点，如：1)靶标可选择性降解，具有催化专一性； 2)弱结合蛋白可转化为选择性PROTAC药物；3)过表达或突变靶标可 降级；以及4)有限的目标交战可导致最大降级。尽管大多数折叠错误和 人类蛋白质组中聚集的蛋白质可以被蛋白酶体系统、一些天然的和突变的蛋白质降解。 易于聚集的蛋白质，如tau寡聚体，对所有已知的蛋白分解途径都具有抵抗力。 自噬或溶酶体途径。高效降解致病牛磺酸的PROTACs的研究进展 Aggates是治疗AD和FTD的一种有吸引力的突破性治疗方法。没有人，无论是业界还是学术界，都没有表现出 为Tau PROTACs在临床上取得成功提供了可靠的数据。传统的PROTAC分析方法，蛋白质印迹 或报告基因分析是耗时、繁琐的，而且容易出现伪影。在这份提案中，我们描述了 一种快速开发Tau PROTAC的高通量方法。促进牛磺酸的PROTAC的研究进展 通过溶酶体/自噬机制进行降解是具有挑战性的。这项拨款提出了筛查战略 不同的E3泛素连接酶对tau蛋白具有去除病原(单体)和聚集体的作用 通过自噬机制。该项目的目标是建立管理致病tau降解的规则， 例如结合在tau聚合体上以区分蛋白酶体和溶酶体的多泛素签名 退化。降解tau聚集体的技术的开发可以直接应用于帕金森病 疾病，亨廷顿病和肌萎缩侧索硬化症。

Novel Approaches for Tau PROTAC Drug Discovery Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) are a group of neurodegenerative diseases characterized by the pathological accumulation of hyper-phosphorylated tau (P-tau) protein, in the form of intracellular paired helical filaments (PHFs) or neurofibrillary tangles (NFTs), or aggregates, within neurons and glia of affected brain regions, leading to cell death. Several approaches to remove aggregates of pathogenic tau have failed, including antibody therapy. Novel approaches to remove aggregated proteins are desired. Targeted protein degradation by PROteolysis TArgeting Chimeras (PROTACs) has emerged as novel therapeutic modality. PROTACs are heterobifunctional small molecules that simultaneously bind to a target protein and a ubiquitin E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present a new opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. PROTAC drugs offer many advantages, such as: 1) target can be selectively degraded with catalytic specificity; 2) weak binders can be converted into selective PROTAC drugs; 3) overexpressed or mutant targets can be degraded; and 4) limited target engagement can lead to maximal degradation. Although most misfolded and aggregated proteins in the human proteome can be degraded by proteasomal system, some native and mutant proteins prone to aggregation, such as tau oligomers are resistant to all known proteolytic pathways thus subject to autophagic or lysosomal pathway. Development of PROTACs that can efficiently degrade pathogenic tau aggregates is an attractive and breakthrough therapy for AD and FTD. No one, industry or academia has shown credible data for tau PROTACs to succeed in the clinic. Traditional methods for PROTAC analysis, western blot or reporter gene analysis are time consuming, cumbersome, and prone to artifacts. In this proposal we describe a high throughput method for rapid development of tau PROTACs. Development of PROTACs that promote tau degradation by lysosomal/autophagic mechanism is challenging. This grant proposes strategies to screening different E3 ubiquitin ligases for tau PROTAC that will remove pathogenic (monomeric) as well as aggregates through autophagic mechanism. Goal of the project is to establish rules that govern pathogenic tau degradations, such as poly-ubiquitin signatures conjugated on tau aggregates to differentiate proteasomal vs lysosomal degradation. Development of the technology that degrades tau aggregates can be directly applied to Parkinson’s disease, Huntingdon disease and Amyotrophic Lateral Scleroses.