BACKGROUND The abnormal assembly of tau into neurofibrillary tangles has been associated with over 30 debilitating disorders known as tauopathies. Tauopathies affect millions of people worldwide, yet no clinically approved solution for tau aggregation is currently available. METHODS We employed a structure-based design approach to make a series of short peptide-based perturbants (Trojans), that can interact with the core hydrophobic fragment of tau protein. Through a combination of various biophysical methods, serum stability, toxicity, and blood-brain barrier translocation assays, we have assessed the efficacy of these designed peptides to intervene the aggregation of tau protein fragment. RESULTS Our observations suggest that Trojan peptides could modulate the aggregation of the Ac-VQIVYK-NH2 peptide by either accelerating or arresting its self-assembly and reduce the neurotoxicity of the fibrils formed. The designed perturbant peptides showed three essential pre-requisites such as negligible cytotoxicity, high proteolytic stability in serum, and an ability to cross human blood-brain barrier (BBB). Furthermore, the Trojans could disassemble the pre-formed fibrillar assemblies. CONCLUSIONS These designed Trojan peptides can serve as a potential therapeutic option for tauopathies, modulating post as well as pre-aggregation leading to the diseases condition. GENERAL SIGNIFICANCE Tauopathies are a group of over 20 progressive neurodegenerative disorders that affect millions of people worldwide. The available therapies of tau-linked neurodegenerative syndromes are limited and mostly symptomatic and therefore there is an urgent need for a cost-effective treatment option. We are presenting a series of structure-based, de novo designed, short peptides that can potentially modulate tau protein aggregation.

中文翻译：

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使用“特洛伊”序列调节 tau 蛋白聚集。

背景技术 tau 异常组装成神经原纤维缠结与 30 多种称为 tau 病变的衰弱性疾病有关。Tauopathies 影响全球数百万人，但目前尚无临床批准的 tau 聚集解决方案。方法 我们采用基于结构的设计方法制作了一系列基于短肽的干扰物（Trojans），它们可以与 tau 蛋白的核心疏水片段相互作用。通过结合各种生物物理方法、血清稳定性、毒性和血脑屏障易位测定，我们评估了这些设计的肽干预 tau 蛋白片段聚集的功效。结果 我们的观察表明，Trojan 肽可以通过加速或阻止其自组装来调节 Ac-VQIVYK-NH2 肽的聚集，并降低形成的原纤维的神经毒性。设计的干扰肽显示出三个基本的先决条件，例如可忽略的细胞毒性、血清中的高蛋白水解稳定性和穿过人血脑屏障 (BBB) 的能力。此外，特洛伊木马可以拆卸预先形成的纤维状组件。结论 这些设计的特洛伊肽可以作为 tau 蛋白病的潜在治疗选择，调节导致疾病状况的后期和预聚集。一般意义 Tauopathies 是一组超过 20 种进行性神经退行性疾病，影响全世界数百万人。与 tau 相关的神经退行性综合征的可用疗法是有限的，并且大多是有症状的，因此迫切需要一种具有成本效益的治疗选择。我们正在展示一系列基于结构的、从头设计的短肽，它们可能会调节 tau 蛋白的聚集。