Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment
Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment
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UNC-51 样激酶 1 (ULK1) 小分子激活剂可诱导细胞保护性自噬，用于帕金森病治疗
DOI：
10.1021/acs.jmedchem.7b01575
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发表时间：
2018-04-12
影响因子：
7.3
通讯作者：
Liu, Bo
中科院分区：
文献类型：
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作者：
Ouyang, Liang;Zhang, Lan;Liu, Bo
UNC-51 样激酶 1 (ULK1) 是酵母 Atg1 直向同源物，是自噬中唯一的丝氨酸-苏氨酸激酶和起始酶 1，可被视为帕金森病 (PD) 的靶点。在此，我们通过基于结构的药物设计发现了一种小分子 33i (BL-918) 作为 ULK1 的有效激活剂。随后，通过定点诱变发现一些关键氨基酸残基（Arg18、Lys50、Asn86 和 Tyr89）对于 ULK1 和 33i 之间的结合口袋至关重要。此外，我们发现 33i 通过 ULK 复合物在 SH-SYSY 细胞中诱导自噬。有趣的是，该激活剂对 MPP+ 处理的 SH-SYSY 细胞显示出细胞保护作用，并通过针对 PD 小鼠模型中 ULK1 调节的自噬来防止 MPTP 诱导的运动功能障碍和多巴胺能神经元丧失。总之，这些结果证明了针对 ULK1 的治疗潜力，而 33i（ULK1 的新型激活剂）可能作为未来 PD 治疗的候选药物。
UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating 1, enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, we discovered a small molecule 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86, and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, we found that 33i induced autophagy via the ULK complex in SH-SYSY cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SYSY cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.