Alzheimer’s Disease (AD) is a neurodegenerative disorder proven to be caused by the aggregation of protein tau into fibrils, resulting in neuronal death. The irreparable neuronal damage leads to irreversible symptoms with no cure; therefore, disaggregation of these tau fibrils could be targeted as a therapeutic approach to AD. Here we have developed a fungal natural product library to screen for secondary metabolites that have bioactive potential towards AD tau. Our initial screenings indicate that penicillic acid demonstrates anti-aggregation activity towards tau, while further in vitro experiments reveal that penicillic acid directly inhibits tau by disaggregating fibrils. Although penicillic acid possesses blood-brain barrier penetrability properties that are computationally predicted to be favorable, it is presumed to contain some mutagenic effects as well. To address this, we used the backbone of penicillic acid as a chemical probe to discover similar compounds that can inhibit AD tau aggregation with limited mutagenicity. This work suggests the potential of discovering chemical probes through natural product screening for small-molecule drug discovery of tauopathies.

中文翻译：

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青霉素作为对抗阿尔茨海默病中 tau 聚集的化学探针的发现


阿尔茨海默病 （AD） 是一种神经退行性疾病，被证明是由蛋白质 tau 聚集成原纤维引起的，导致神经元死亡。无法修复的神经元损伤会导致无法治愈的不可逆症状;因此，这些 tau 原纤维的解聚可以作为 AD 的治疗方法。在这里，我们开发了一个真菌天然产物库，用于筛选对 AD tau 具有生物活性潜力的次生代谢物。我们的初步筛选表明，青霉素酸表现出对 tau 的抗聚集活性，而进一步的体外实验表明，青霉素酸通过解聚原纤维直接抑制 tau。尽管青霉素具有血脑屏障穿透性特性，计算预测为有利的，但据推测它也包含一些诱变作用。为了解决这个问题，我们使用青霉素酸的主链作为化学探针，发现了可以抑制 AD tau 聚集且致突变性有限的类似化合物。这项工作表明，通过天然产物筛选发现化学探针的潜力，用于 tau 蛋白病的小分子药物发现。