Novel inhibitor of influenza non-structural protein 1 blocks multi-cycle replication in an RNase L-dependent manner.
Novel inhibitor of influenza non-structural protein 1 blocks multi-cycle replication in an RNase L-dependent manner.
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DOI：
10.1099/vir.0.025015-0
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发表时间：
2011-01
期刊：
影响因子：
--
通讯作者：
Engel DA
中科院分区：
文献类型：
--
作者：
Walkiewicz MP;Basu D;Jablonski JJ;Geysen HM;Engel DA
流感病毒非结构蛋白1（NS1）是病毒对宿主干扰素（IFN）系统应答的核心。NS1已被证明是一个潜在的治疗靶点，通过识别特定的小分子抑制剂的抗病毒治疗。本研究揭示了一种新的NS1拮抗剂的生物学机制。化合物JJ3297抑制病毒复制超过三个数量级，而不影响细胞活力。重要的是，它有效地逆转了NS1诱导的IFN mRNA产生抑制。该假设被测试，即JJ3297促进IFN在感染细胞中的产生，从而保护周围未感染的细胞。因此，该化合物在以非常低的m.o.i. 与假设一致，该化合物对高m.o.i.启动的6小时单周期感染没有可检测的影响。 JJ3297对病毒复制的影响不是通过抑制NS1表达或其在细胞中的错误定位引起的。JJ3297促进IFN样抗病毒状态的诱导，导致对随后的水泡性口炎病毒攻击的抗性增加。JJ3297的活性绝对需要细胞RNase L的功能，表明该化合物的功能需要完整的IFN系统。这些结果支持了一种模型，其中抑制NS1功能导致恢复IFN诱导的抗病毒状态和抑制病毒复制和传播。这代表了抗流感病毒药物开发的新方向，即利用IFN途径来挑战病毒复制。
Influenza virus non-structural protein 1 (NS1) is the centrepiece of the viral response to the host interferon (IFN) system. NS1 has been demonstrated previously to be a potential therapeutic target for antiviral therapy by identification of specific small-molecule inhibitors. This study demonstrated the biological mechanism for a potent new NS1 antagonist. Compound JJ3297 inhibited virus replication by more than three orders of magnitude without affecting cell viability. Importantly, it efficiently reversed NS1-induced inhibition of IFN mRNA production. The hypothesis was tested that JJ3297 facilitates IFN production in infected cells, leading to protection of the surrounding uninfected cells. Accordingly, the compound efficiently prevented virus spread through a cell population during a 48 h multi-cycle infection initiated at a very low m.o.i. Consistent with the hypothesis, the compound had no detectable influence on a 6 h single-cycle infection initiated at a high m.o.i. The effect of JJ3297 on virus replication was not caused by inhibition of NS1 expression or its mislocalization in the cell. JJ3297 facilitated the induction of an IFN-like antiviral state, resulting in increased resistance to subsequent challenge with vesicular stomatitis virus. The activity of JJ3297 absolutely required the function of cellular RNase L, indicating that an intact IFN system is required for function of the compound. These results support a model in which inhibition of NS1 function results in restoration of the IFN-induced antiviral state and inhibition of virus replication and spread. This represents a new direction for anti-influenza virus drug development that exploits the IFN pathway to challenge virus replication.
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影响因子：
2.2
作者：
Chambers TM;Quinlivan M;Sturgill T;Cullinane A;Horohov DW;Zamarin D;Arkins S;García-Sastre A;Palese P
通讯作者：
Palese P
DOI：
10.1073/pnas.031575198
发表时间：
2001-02-27
影响因子：
11.1
作者：
Basler, CF;Reid, AH;Taubenberger, JK
通讯作者：
Taubenberger, JK
影响因子：
3.7
作者：
KOENNECKE, I;BOSCHEK, CB;SCHOLTISSEK, C
通讯作者：
SCHOLTISSEK, C
影响因子：
5.4
作者：
Egorov, A;Brandt, S;Muster, T
通讯作者：
Muster, T
影响因子：
11.4
作者：
Chen, ZY;Li, YZ;Krug, RM
通讯作者：
Krug, RM