Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery.
Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery.
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通过基于片段的药物发现鉴定 RNase L 小分子抑制剂
DOI：
10.1021/acs.jmedchem.1c01156
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发表时间：
2022-01-27
影响因子：
7.3
通讯作者：
Huang, Hao
中科院分区：
文献类型：
--
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
假激酶-核糖核酸内切酶RNase L在抗病毒先天免疫中起重要作用，并且还涉及许多其他细胞活动。RNase L的抑制显示出对Aicardi-Goutières综合征（AGS）的治疗潜力。因此，RNase L是一个很有前途的药物靶点。在本研究中，我们使用酶分析和核磁共振筛选，发现了13个抑制片段对RNase L。确定了RNA酶L与两个片段复合的共晶体结构，并且两个片段都结合到假激酶结构域的ATP结合口袋。杨梅苷、牡荆素和金丝桃苷这三种天然产物与片段AC 40357具有相似的骨架结构，在体外表现出较强的抑制活性。此外，杨梅素具有很好的细胞抑制活性。核糖核酸酶L与杨梅素的共晶体结构为通过变构调节其核糖核酸酶活性来设计抑制剂提供了结构基础。我们的研究结果表明，片段筛选可以导致RNase L的天然产物抑制剂的发现。
The pseudokinase-endoribonuclease RNase L plays important roles in antiviral innate immunity and is also implicated in many other cellular activities. 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. Co-crystal structures of RNase L in complex with two fragments were determined, and both fragments bind to the ATP-binding pocket of the pseudokinase domain. Myricetin, vitexin and hyperoside, three natural products sharing similar scaffolds with the fragment AC40357, demonstrated potent inhibitory activity in vitro. In addition, myricetin has promising cellular inhibitory activity. A co-crystal structure of RNase L with myricetin provided a structural basis for inhibitor design by allosterically modulating its rnase activity. Our findings demonstrate that fragment screening can lead to the discovery of natural product inhibitors of RNase L.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.7
作者：
Holder, Sheldon;Zemskova, Marina;Lilly, Michael B.
通讯作者：
Lilly, Michael B.
影响因子：
4.6
作者：
Lee MK;Lee KH;Yoo SH;Park CY
通讯作者：
Park CY
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
5.9
作者：
Drappier M;Michiels T
通讯作者：
Michiels T