Institute of Basic and Translational Medicine & Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, No.1 Xinwang Road, Xi'an 710021, PR China.
School of Basic Medical Science, Xi'an Medical University, Xi'an, 710021, China.
Mol Cell Neurosci. 2021 Jul;114:103630. doi: 10.1016/j.mcn.2021.103630. Epub 2021 May 21.
LilrB2 is an Aβ receptor with high affinity, which not only contributes to memory deficits but also mediates the loss of synaptic plasticity. Thus, Aβ-LilrB2 interaction inhibitors (ALIs) might be a potential therapeutic strategy for Alzheimer's disease. In this study, an ELISA-based interaction assay was established as a novel approach to identify ALIs and was used to screen 110 compounds from a compound library. Among the 110 compounds, four compounds presented IC values lower than the positive control flusipirilene. The two phenyl-1,3,5-triazine derivatives (compound 103 and 104) displayed inhibitory activities with the IC of 0.23 μM and 0.05 μM respectively. The neuroprotection activities of the hit compounds were evaluated in SH-SY5Y cell line. Compound 104 presented good safety and neuroprotective effects against Aβ. Further study of its effect on the downstream pathway of Aβ indicated that compound 104 was able to reverse the Aβ induced cofilin dephosphorylation, tau hyperphosphorylation and neurite outgrowth inhibition. The docking study showed that fluspirilene and compound 104 were favorably positioned into the Ben 3 and 4 binding pockets via their aromatic ring, which was similar to that reported for Aβ. Based on these facts, compound 104 can be identified as a potential ALI which might be of therapeutic importance for AD treatment.
LilrB2 是一种具有高亲和力的 Aβ 受体，不仅导致记忆缺陷，还介导突触可塑性的丧失。因此，Aβ-LilrB2 相互作用抑制剂（ALIs）可能是阿尔茨海默病的一种潜在治疗策略。在这项研究中，建立了一种基于 ELISA 的相互作用测定法，作为一种新方法来鉴定 ALIs，并用于从化合物文库中筛选 110 种化合物。在 110 种化合物中，有 4 种化合物的 IC 值低于阳性对照物氟西匹仑。两种苯-1,3,5-三嗪衍生物（化合物 103 和 104）显示出抑制活性，IC 值分别为 0.23 μM 和 0.05 μM。在 SH-SY5Y 细胞系中评估了命中化合物的神经保护活性。化合物 104 对 Aβ 具有良好的安全性和神经保护作用。进一步研究其对 Aβ 下游途径的影响表明，化合物 104 能够逆转 Aβ 诱导的丝切蛋白去磷酸化、tau 过度磷酸化和神经突生长抑制。对接研究表明，氟西匹仑和化合物 104 通过其芳环有利地定位到 Ben 3 和 4 结合口袋中，这与报道的 Aβ 相似。基于这些事实，化合物 104 可以被鉴定为一种潜在的 ALI，这可能对 AD 的治疗具有重要意义。
