Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity.
Rocaglates as Antivirals: Comparing the Effects on Viral Resistance, Anti-Coronaviral Activity, RNA-Clamping on eIF4A and Immune Cell Toxicity.
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作为抗病毒药：比较对病毒耐药性，抗核心病毒活性的影响，对EIF4A的RNA钳位和免疫细胞毒性的影响。
DOI：
10.3390/v14030519
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发表时间：
2022-03-03
期刊：
影响因子：
--
通讯作者：
Grünweller A
中科院分区：
文献类型：
--
作者：
Obermann W;Friedrich A;Madhugiri R;Klemm P;Mengel JP;Hain T;Pleschka S;Wendel HG;Hartmann RK;Schiffmann S;Ziebuhr J;Müller C;Grünweller A
Rocaglates是一种有效的广谱抗病毒化合物，具有良好的安全性。它们通过将mRNAs的5‘-UTRs夹在RNA解旋酶eIF4A的表面来抑制不同RNA病毒的病毒蛋白质合成。除了天然的岩石粉以外，还开发了合成的岩石粉或CR-1-31-B。在这里，我们比较了岩藻酸盐对病毒5‘-UTR介导的报告基因表达和与eIF4A-多嘌呤复合体结合的影响。此外，我们分析了岩藻酸盐对几种人类免疫细胞的细胞毒性，并比较了它们在冠状病毒感染细胞中的抗病毒活性。最后，通过传代人类冠状病毒229E(HCoV-229E)来评估在MRC-5细胞中增加罗卡酸盐浓度的情况下产生病毒耐药性的可能性。重要的是，没有观察到摇头丸敏感性的下降，这表明如果宿主因子eIF4A是靶点，病毒逃逸突变不太可能出现。综上所述，这三种岩藻酸盐都是很有前景的抗病毒药物，但在对人类免疫细胞的细胞毒性、RNA钳制效率和抗病毒活性方面存在差异。具体来说，与西维斯特和CR-1-31-B相比，佐他芬显示出较低的RNA钳制效率和抗病毒活性，但对免疫细胞的细胞毒性较小。我们的结果强调了罗卡酸盐作为广谱抗病毒药物的潜力，没有迹象表明HCoV-229E出现逃逸突变。
Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5′-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5′-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.
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DOI：
10.3390/v10040149
发表时间：
2018-03-27
期刊：
Viruses
影响因子：
--
作者：
Elgner F;Sabino C;Basic M;Ploen D;Grünweller A;Hildt E
通讯作者：
Hildt E
影响因子：
8.8
作者：
Dittmar M;Lee JS;Whig K;Segrist E;Li M;Kamalia B;Castellana L;Ayyanathan K;Cardenas-Diaz FL;Morrisey EE;Truitt R;Yang W;Jurado K;Samby K;Ramage H;Schultz DC;Cherry S
通讯作者：
Cherry S
影响因子：
--
作者：
Patton JT;Lustberg ME;Lozanski G;Garman SL;Towns WH;Drohan CM;Lehman A;Zhang X;Bolon B;Pan L;Kinghorn AD;Grever MR;Lucas DM;Baiocchi RA
通讯作者：
Baiocchi RA
影响因子：
5.9
作者：
Bauer L;Lyoo H;van der Schaar HM;Strating JR;van Kuppeveld FJ
通讯作者：
van Kuppeveld FJ
影响因子：
4.5
作者：
Gupta, Sneha V.;Sass, Ellen J.;Lucas, David M.
通讯作者：
Lucas, David M.