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LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-03-30 , DOI: 10.1021/acs.jmedchem.0c00416
Deepak Bhattarai 1 , Min Jae Lee 1 , Ahruem Baek 2 , In Jun Yeo 3 , Zachary Miller 1 , Yu Mi Baek 2 , Sukyeong Lee 4 , Dong-Eun Kim 2 , Jin Tae Hong 3 , Kyung Bo Kim 1
Affiliation  

The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates cognitive impairments in mouse models of Alzheimer’s disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1α production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.

中文翻译:

LMP2抑制剂可作为阿尔茨海默氏病的潜在治疗方法。

免疫蛋白酶体(iP)是一种可诱导的蛋白酶体变体,具有三个免疫亚基,低分子量多肽2(LMP2),多催化内肽酶复合物亚基1和低分子量多肽7(LMP7),参与炎症反应的多个方面。我们最近报道,YU102是iP亚基LMP2和组成型蛋白酶体催化亚基β1的双重抑制剂,可独立于淀粉样蛋白沉积而改善阿尔茨海默氏病(AD)小鼠模型的认知障碍。为了研究LMP2的抑制作用是否足以改善AD小鼠的认知功能,在这里我们制备了37种YU102类似物,并确定了有效的LMP2抑制剂DB-310(28)(IC 50:80.6 nM),在过表达ABCB1转运蛋白的细胞中具有更高的选择性和通透性。我们表明,DB-310诱导小胶质细胞中IL-1α产生的抑制并改善AD的Tg2576转基因小鼠模型中的认知功能。这项研究支持LMP2的抑制是一种有前途的治疗AD的治疗策略。
更新日期:2020-03-30
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