Prion Disease Therapeutics

朊病毒疾病是影响哺乳动物（包括人类）的神经退行性疾病，并且在单体细胞朊病毒蛋白（PrPC）转化为聚集的羊瘙痒病形式（PrPSc）后出现。没有治疗朊病毒疾病的疗法，鉴定结合PrPC的化合物，防止其转化为PrPSc，是一种可行的治疗策略。我们设计并合成了六个新的三甲氧基苯甲酰胺类抗朊病毒药物候选物。分子对接分析预测，所有的衍生物结合到一个热点区域位于PrP球状结构域具有非常相似的空间取向和相互作用模式。尽管在无细胞转化测定中没有类似物抑制重组PrP（rPrP）的体外聚集，但RT-QuIC化合物8a加速rPrP转化为PrPSc样物质。STD-NMR和ITC分析表明，8a和8b均与rPrP 90231结合。这些类似物对PrPSc感染的细胞系是有毒的，因此我们不能通过使用这种细胞方法来评估它们的抗朊病毒活性，尽管这种毒性是细胞系依赖性的。这些结果指出，本文所述的4-氨基-喹啉三甲氧基-苯甲酰胺支架代表了一种新的化学模式，其可用作在具有改善的亲和力和安全性特征的PrP配体的设计中进行未来结构优化的起点。

Prion diseases are neurodegenerative disorders which affect mammals, including the human species, and arise after the conversion of the monomeric cellular prion protein (PrPC) into the aggregated scrapie form (PrPSc). There is no therapy to treat prion diseases and the identification of compounds that bind PrPC, preventing its conversion into PrPSc, is a viable therapeutic strategy. We designed and synthesized six novel trimethoxy-benzamide compounds as anti-prion drug candidates. Molecular docking analyses predicted that all the derivatives bind to a hotspot region located in the PrP globular domain with very similar spatial orientation and interaction mode. Although none of the analogs inhibited in vitro-aggregation of recombinant PrP (rPrP) in a cell-free conversion assay, the RT-QuIC, compound 8a accelerated rPrP conversion into PrPSc-like species. STD-NMR and ITC analyses indicated that both 8a and 8b bind to rPrP90231. These analogs were toxic to PrPSc-infected cell lines, hence we could not assess their anti-prion activity by using this cellular approach, although this toxicity was cell line-dependent. These results point out that the 4-amino-quinoline trimethoxy-benzamide scaffold described herein represents a novel chemical pattern useful as a starting point for future structural optimization in the design of PrP ligands with improved affinity and safety profiles.