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
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页码：20467 / 20477
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