School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland.
Viikki Metabolomics Unit, Department of Biosciences, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland.
J Med Chem. 2023 Jun 8;66(11):7475-7496. doi: 10.1021/acs.jmedchem.3c00235. Epub 2023 May 29.
Prolyl oligopeptidase (PREP) is a widely distributed serine protease in the human body cleaving proline-containing peptides; however, recent studies suggest that its effects on pathogenic processes underlying neurodegeneration are derived from direct protein-protein interactions (PPIs) and not from its regulation of certain neuropeptide levels. We discovered novel nonpeptidic oxazole-based PREP inhibitors, which deviate from the known structure-activity relationship for PREP inhibitors. These new compounds are effective modulators of the PPIs of PREP, reducing α-synuclein (αSyn) dimerization and enhancing protein phosphatase 2A activity in a concentration-response manner, as well as reducing reactive oxygen species production. From the best performing oxazoles, was selected for studies. Its brain penetration was evaluated, and it was tested in αSyn virus vector-based and αSyn transgenic mouse models of Parkinson's disease, where it restored motor impairment and reduced levels of oligomerized αSyn in the striatum and .
脯氨酰寡肽酶（PREP）是人体内广泛分布的丝氨酸蛋白酶，可切割含脯氨酸的肽；然而，最近的研究表明，其对神经退行性疾病发病机制的影响源于直接的蛋白质-蛋白质相互作用（PPIs），而不是通过调节特定神经肽水平实现的。我们发现了新型非肽基噁唑类 PREP 抑制剂，这些抑制剂偏离了已知的 PREP 抑制剂结构-活性关系。这些新化合物是 PREP 的有效 PPI 调节剂，可浓度依赖性地降低α-突触核蛋白（αSyn）二聚体形成并增强蛋白磷酸酶 2A 活性，同时还能减少活性氧的产生。从表现最佳的噁唑类化合物中，选择 进行进一步研究。评估了其脑穿透性，并在基于 αSyn 病毒载体和 αSyn 转基因帕金森病小鼠模型中进行了测试，结果显示其可恢复运动障碍，并降低纹状体和 中寡聚化 αSyn 的水平。
