L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases p-amyloid peptide production in HEK293-APPswe cells | |
Lu Qin1; Chen Wuyan2; Zhu Zhiyuan2; Chen Jing2; Xu Yechun2; Kaewpet Morakot3; Rukachaisirikul Vatcharin3; Chen Lili2; Shen Xu1 | |
刊名 | Acta Pharmacologica Sinica |
2012 | |
卷号 | 33期号:12页码:1459 |
关键词 | L655 240 Alzheimer's disease BACE1 -amyloid peptide HEK293-APPswe cells |
ISSN号 | 1671-4083 |
英文摘要 | To identify a small molecule L655,240 as a novel -secretase (BACE1) inhibitor and to investigate its effects on -amyloid (A) generation in vitro. Methods: Fluorescence resonance energy transfer (FRET) was used to characterize the inhibitory effect of L655,240 on BACE1. Sur-face plasmon resonance (SPR) technology-based assay was performed to study the binding affinity of L655,240 for BACE1. The selectivity of L655,240 toward BACE1 over other aspartic proteases was determined with enzymatic assay. The effects of L655,240 on A40, A42, and sAPP production were studied in HEK293 cells stably expressing APP695 Swedish mutantK595N/M596L (HEK293-APPswe cells). The activities of BACE1, y-secretase and a-secretase were assayed, and both the mRNA and protein levels of APP and BACE1 were evaluated using real-time PCR (RT-PCR) and Western blot analysis. Results: L655,240 was determined to be a competitive, selective BACE1 inhibitor (IC50=4.471.37 mol/L), which bound to BACE1 directly (KD=17.90.72 mol/L). L655,240 effectively reduced A40, A42, and sAPP production by inhibiting BACE1 without affecting the activities of y-secretase and a-secretase in HEK293-APPswe cells. L655,240 has no effect on APP and BACE1 mRNA or protein levels in HEK293-APPswe cells. Conclusion: The small molecule L655,240 is a novel BACE1 inhibitor that can effectively decreases A production in vitro, thereby highlighting its therapeutic potential for the treatment of Alzheimer's disease. |
语种 | 英语 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/294296] |
专题 | 中国科学院上海药物研究所 |
作者单位 | 1.华东理工大学 2.中国科学院上海药物研究所 3.宋卡王子大学 |
推荐引用方式 GB/T 7714 | Lu Qin,Chen Wuyan,Zhu Zhiyuan,et al. L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases p-amyloid peptide production in HEK293-APPswe cells[J]. Acta Pharmacologica Sinica,2012,33(12):1459. |
APA | Lu Qin.,Chen Wuyan.,Zhu Zhiyuan.,Chen Jing.,Xu Yechun.,...&Shen Xu.(2012).L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases p-amyloid peptide production in HEK293-APPswe cells.Acta Pharmacologica Sinica,33(12),1459. |
MLA | Lu Qin,et al."L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases p-amyloid peptide production in HEK293-APPswe cells".Acta Pharmacologica Sinica 33.12(2012):1459. |
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