Abstract：
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Bhattarai D,Lee MJ,Baek A,Yeo IJ,Miller Z,Baek YM,Lee S,Kim DE,Hong JT,Kim KBdoi
10.1021/acs.jmedchem.0c00416subject
Has Abstractpub_date
2020-04-09 00:00:00pages
3763-3783issue
7eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:A series of peptidyl alpha-ketoacids and alpha-ketoesters was synthesized and studied as mu-calpain inhibitors. Docking studies revealed that the mu-calpain inhibitory activity of the compounds is influenced by hydrogen bonding interactions and the potential for ionic interaction with active site residues as well as p...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm00352a025
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pub_type： 杂志文章
doi：10.1021/jm00224a020
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pub_type： 杂志文章
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更新日期：2012-11-26 00:00:00
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journal_title：Journal of medicinal chemistry
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doi：10.1021/jm00063a013
更新日期：1993-05-28 00:00:00
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pub_type： 杂志文章
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pub_type： 杂志文章
doi：10.1021/jm00048a021
更新日期：1994-10-28 00:00:00
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doi：10.1021/acs.jmedchem.8b00783
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pub_type： 杂志文章
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