Discovery of the Lysosome-Inhibiting Function of Acremolactone B

IF 17.7 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2024-05-13 DOI:10.1055/a-2325-3938

Shaonan Wang, Yali Wu, Mengyu Ba, Zhou Xu, Guoxing Gu, William G. Whittingham, Cong Liu, Ang Li, Weiwei He

引用次数: 0

Abstract

Lysosome inhibitors have garnered considerable interest for their utility in lysosome biology research and potential therapeutic applications. We discovered the lysosome-inhibiting function of acremolactone B (1), a scarce azaphilone-type polyketide, leveraging our previous scalable synthesis. This compound significantly reduces lysosomal acidity and impairs the maturation of the lysosomal protease cathepsin D (CTSD) in triple-negative breast cancer cells (MDA-MB-231) and human lung cancer cells (A549). Furthermore, we found that compound 1 suppresses downstream autophagy, as revealed by monitoring autophagic flux and conducting transmission electron microscopy (TEM) analysis. This study unveils the previously unrecognized biological role of 1 and introduces a new scaffold for lysosome inhibitors.

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发现 Acremolactone B 的溶酶体抑制功能

溶酶体抑制剂因其在溶酶体生物学研究和潜在治疗应用中的作用而备受关注。我们利用以前的可扩展合成技术，发现了一种稀缺的萘甲内酯类多酮化合物--吖丙内酯 B (1)的溶酶体抑制功能。在三阴性乳腺癌细胞（MDA-MB-231）和人类肺癌细胞（A549）中，这种化合物能明显降低溶酶体酸度，并损害溶酶体蛋白酶 cathepsin D（CTSD）的成熟。此外，通过监测自噬通量和进行透射电子显微镜（TEM）分析，我们发现化合物 1 能抑制下游自噬。这项研究揭示了 1 以前未被发现的生物学作用，并为溶酶体抑制剂引入了一个新的支架。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.

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