南方科技大学知识苑(SUSTech KC): Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery

题名	Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery
作者	Tang，Jinle 1; Dong，Beihua 2; Liu，Ming 1; Liu，Shuyan 3; Niu，Xiaogang 4; Gaughan，Christina 2; Asthana，Abhishek 2; Zhou，Huan 5; Xu，Zhengshuang 1; Zhang，Guoliang 3; Silverman，Robert H.2; Huang，Hao 1
通讯作者	Silverman，Robert H.; Huang，Hao
发表日期	2021
DOI	10.1021/acs.jmedchem.1c01156
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY 影响因子和分区
ISSN	0022-2623
EISSN	1520-4804
卷号	65 期号:2
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-Goutières 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.
相关链接	[Scopus记录]
收录类别	SCI
语种	英语
学校署名	其他
资助项目	National Natural Science Foundation of China[21778008,22107009] ; Shenzhen Science and Technology Program["KQTD20190929174023858","JCYJ2020210940401752"] ; National Institute of Allergy and Infectious Diseases of the National Institutes of Health[R01AI135922]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000766751000025
出版者	AMER CHEMICAL SOC
ESI学科分类	CHEMISTRY
Scopus记录号	2-s2.0-85120637798
来源库	Scopus
引用统计	被引频次[WOS]：8
成果类型	期刊论文
条目标识符	http://sustech.caswiz.com/handle/2SGJ60CL/258172
专题	南方科技大学第二附属医院
作者单位	1.State Key Laboratory of Chemical Oncogenomics,Laboratory of Structural Biology and Drug Discovery,School of Chemical Biology and Biotechnology,Peking University,Shenzhen Graduate School,Shenzhen,518055,China 2.Department of Cancer Biology,Lerner Research Institute,Cleveland Clinic,Cleveland,44195,United States 3.National Clinical Research Center for Infectious Diseases,Shenzhen Third People's Hospital,Southern University of Science and Technology,Shenzhen,518112,China 4.College of Chemistry and Molecular Engineering,Beijing Nuclear Magnetic Resonance Center,Peking University,Beijing,100871,China 5.Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai,201204,China
推荐引用方式 GB/T 7714	Tang，Jinle,Dong，Beihua,Liu，Ming,et al. Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,65(2).
APA	Tang，Jinle.,Dong，Beihua.,Liu，Ming.,Liu，Shuyan.,Niu，Xiaogang.,...&Huang，Hao.(2021).Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery.JOURNAL OF MEDICINAL CHEMISTRY,65(2).
MLA	Tang，Jinle,et al."Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery".JOURNAL OF MEDICINAL CHEMISTRY 65.2(2021).