Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors

Yang Yiqing; Cao Lin; Gao Hongying; Wu Yue; Wang Yaxin; Fang Fang; Lan Tianlong; Lou Zhiyong; Rao Yu

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Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors

机译：新型有效广谱抗病毒抑制剂的发现，优化和目标鉴定

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Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.

机译：病毒感染正在增加，可能是持久的全球风险。在本研究中，通过表型筛选利用化学文库来发现新的抗病毒抑制剂。从铅优化后，鉴定了一种新型有效的小分子（Ryl-634），显示出对各种致病病毒的优异的广谱抑制活性，包括丙型肝炎病毒，登革病毒，Zika病毒，Chikungunya病毒，肠道病毒71，人免疫缺陷病毒，呼吸道合胞病毒等。通过基于活性的蛋白质分析和其他技术的组合进一步探索Ryl-634的作用机制和潜在靶标。最后，将人二氢脱氢酶验证为Ryl-634的主要靶标。我们在使用Ryl-634的压力选择下没有观察到任何突变抗性，并且它与一些食物和药物管理局批准的药物具有强烈的协同效应。因此，基于Ryl-634开发新的广谱抗病毒的可能性很大。

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《Journal of Medicinal Chemistry》 |2019年第8期|共18页
作者
Yang Yiqing; Cao Lin; Gao Hongying; Wu Yue; Wang Yaxin; Fang Fang; Lan Tianlong; Lou Zhiyong; Rao Yu;
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作者单位

Tsinghua Univ MOE Key Lab Prot Sci Sch Pharmaceut Sci MOE Key Lab Bioorgan Phosphorus Chem &

Chem Biol Beijing 100084 Peoples R China;

Nankai Univ Coll Life Sci Tianjin 300071 Peoples R China;

Tsinghua Univ MOE Key Lab Prot Sci Sch Pharmaceut Sci MOE Key Lab Bioorgan Phosphorus Chem &

Chem Biol Beijing 100084 Peoples R China;

Tsinghua Univ MOE Key Lab Prot Sci Sch Pharmaceut Sci MOE Key Lab Bioorgan Phosphorus Chem &

Chem Biol Beijing 100084 Peoples R China;

Hebei Normal Univ Coll Life Sci Shijiazhuang 050024 Hebei Peoples R China;

Tsinghua Univ MOE Key Lab Prot Sci Sch Pharmaceut Sci MOE Key Lab Bioorgan Phosphorus Chem &

Chem Biol Beijing 100084 Peoples R China;

Tsinghua Univ MOE Key Lab Prot Sci Sch Pharmaceut Sci MOE Key Lab Bioorgan Phosphorus Chem &

Chem Biol Beijing 100084 Peoples R China;

Tsinghua Univ Sch Med Beijing 100084 Peoples R China;

Tsinghua Univ MOE Key Lab Prot Sci Sch Pharmaceut Sci MOE Key Lab Bioorgan Phosphorus Chem &

Chem Biol Beijing 100084 Peoples R China;

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正文语种 eng
中图分类药学;
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1. Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors [J] . Yang Yiqing, Cao Lin, Gao Hongying, Journal of Medicinal Chemistry . 2019,第8期

机译：新型有效广谱抗病毒抑制剂的发现，优化和目标鉴定
2. Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity [J] . TariL.W., TrzossM., BensenD.C., Bioorganic and Medicinal Chemistry Letters . 2013,第5期

机译：DNA旋转酶B（GyrB）和拓扑异构酶IV（PARE）的吡咯哒嘧啶抑制剂。第一部分：结构引导和优化双靶向剂，具有效率，广谱酶活性
3. Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity [J] . TariL.W., TrzossM., BensenD.C., Bioorganic and Medicinal Chemistry Letters . 2013,第5期

机译：DNA促旋酶B（GyrB）和拓扑异构酶IV（ParE）的吡咯并嘧啶抑制剂。第一部分：结构导向的发现和具有强力，广谱酶活性的双重靶向剂的优化
4. Design and Discovery of Diarylpyridines and Diarylanilines as Novel Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors [C] . Bingjie Qin, Xingtao Tian, Xingkai Jiang, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：二芳基吡啶和二芳基苯胺作为新型有效的非核苷HIV-1逆转录酶抑制剂的设计和发现
5. Antifungal drug discovery: Identification and characterization of potent, broad-spectrum antifungal compounds via a yeast reporter bioassay. [D] . Tebbets, Bradley Mark. 2012

机译：抗真菌药物的发现：通过酵母报告生物测定法鉴定和表征有效的广谱抗真菌化合物。
6. In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses [O] . Yuanxiang Wang, Yanmei Hu, Shuting Xu, -1

机译：AM2-S31N通道阻滞剂的体外药代动力学优化可导致发现具有抗药性甲型流感病毒的强抗病毒活性的慢结合抑制剂
7. Correction to: Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2 [O] . Rui Xiong, Leike Zhang, Shiliang Li, 2020

机译：校正：靶向Dhodh的新颖和有效的抑制剂是针对RNA病毒的广谱抗病毒，包括新出现的冠状病毒SARS-COV-2

Discovery, Optimization, and Target Identification of Novel Potent Broad-Spectrum Antiviral Inhibitors

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