Discovery of penicillic acid as a chemical probe against tau aggregation in Alzheimer's disease

被引：0

作者：

Shyong, Jennifer ^{[1
]}

Wang, Jinliang ^{[1
]}

Huynh, Quoc-Dung Tran ^{[4
]}

Fayzullina, Marina ^{[1
]}

Yuan, Bo ^{[1
]}

Lee, Ching-Kuo ^{[3
,4
]}

Minehan, Thomas ^{[5
]}

Seidler, Paul M. ^{[1
]}

Wang, Clay C. C. ^{[1
,2
]}

机构：

[1] Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles,CA,90089, United States

[2] Department of Chemistry, University of Southern California, Dornsife College of Letters, Arts and Sciences, Los Angeles,CA,90089, United States

[3] School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei,11031, Taiwan

[4] PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei,11031, Taiwan

[5] Department of Chemistry and Biochemistry, California State University, Northridge, Northridge,CA,91330, United States

来源：

Chemical Science | 2024年 / 15卷 / 48期

关键词：

Alzheimer's Disease (AD) is a neurodegenerative disorder proven to be caused by the aggregation of protein tau into fibrils; resulting in neuronal death. The irreparable neuronal damage leads to irreversible symptoms with no cure; therefore; disaggregation of these tau fibrils could be targeted as a therapeutic approach to AD. Here we have developed a fungal natural product library to screen for secondary metabolites that have bioactive potential towards AD tau. Our initial screenings indicate that penicillic acid demonstrates anti-aggregation activity towards tau; while further in vitro experiments reveal that penicillic acid directly inhibits tau by disaggregating fibrils. Although penicillic acid possesses blood-brain barrier penetrability properties that are computationally predicted to be favorable; it is presumed to contain some mutagenic effects as well. To address this; we used the backbone of penicillic acid as a chemical probe to discover similar compounds that can inhibit AD tau aggregation with limited mutagenicity. This work suggests the potential of discovering chemical probes through natural product screening for small-molecule drug discovery of tauopathies. © 2024 The Royal Society of Chemistry;

D O I：

10.1039/d4sc05469e

中图分类号：

学科分类号：

摘要：

引用

页码：20467 / 20477

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