Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery
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作者
Tang, Jinle; Dong, Beihua; Liu, Ming; Liu, Shuyan; Niu, Xiaogang; Gaughan, Christina; Asthana, Abhishek; Zhou, Huan; Xu, Zhengshuang; Zhang, Guoliang; Silverman, Robert H.; Huang, Hao
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刊物名称
JOURNAL OF MEDICINAL CHEMISTRY
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年、卷、文献号
2022, 65, 0022-2623
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关键词
Tang, Jinle; Dong, Beihua; Liu, Ming; Liu, Shuyan; Niu, Xiaogang; Gaughan, Christina; Asthana, Abhishek; Zhou, Huan; Xu, Zhengshuang; Zhang, Guoliang; Silverman, Robert H.; Huang, Hao
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摘要
The pseudokinase-endoribonuclease RNase L plays important roles in antiviral innate immunity and is also implicated in many other cellular activities. The inhibition of RNase L showed therapeutic potential for Aicardi-Goutie`res syndrome (AGS). Thus, RNase L is a promising drug target. In this study, using an enzyme assay and NMR screening, we discovered 13 inhibitory fragments against RNase L. Cocrystal structures of RNase L separately complexed with two different fragments were determined in which both fragments bound to the ATP-binding pocket of the pseudokinase domain. Myricetin, vitexin, and hyperoside, three natural products sharing similar scaffolds with the fragment AC40357, demonstrated a potent inhibitory activity in vitro. In addition, myricetin has a promising cellular inhibitory activity. A cocrystal structure of RNase L with myricetin provided a structural basis for inhibitor design by allosterically modulating the ribonuclease activity. Our findings demonstrate that fragment screening can lead to the discovery of natural product inhibitors of RNase L.
