Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1.
Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1.
复制标题
流感病毒蛋白 NS1 的新型小分子抑制剂的设计、合成和评估。
DOI：
10.1016/j.bmc.2011.10.026
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发表时间：
2012-01-01
影响因子：
3.5
通讯作者：
Geysen, H. Mario
中科院分区：
文献类型：
--
作者：
Jablonski, Joseph J.;Basu, Dipwanita;Engel, Daniel A.;Geysen, H. Mario
流感是一个持续的世界性公共卫生问题，在季节性流行和零星流行期间会导致显著的发病率和死亡率。现有的疫苗接种计划每年都有不同的效果，对现有抗病毒药物的耐药性是一个日益严重的问题，这使得开发更多的抗病毒药物成为一个重要的挑战。流感病毒非结构蛋白1(NS1)是病毒对宿主干扰素系统反应的核心。先前通过鉴定特定的小分子抑制物，NS1被证明是抗病毒治疗的潜在治疗靶点。对一种抑制化合物NSC125044进行了化学评价。最初的合成工作包括通过去除不需要的功能和确定对活动重要的关键特征来简化核心结构。设计和合成了几个亚类分子，以进一步探索活性并为构效关系奠定基础。根据病毒复制试验中的活性判断，某些类似物的表观效力显著增加，没有细胞毒性。结果表明，靶结合位点既能容忍疏水体积，又能偏好弱碱性取代基。
Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The existing vaccination program is variably effective from year to year, and drug resistance to available antivirals is a growing problem, making the development of additional antivirals an important challenge. Influenza virus non-structural protein 1 (NS1) is the centerpiece of the viral response to the host interferon (IFN) system. NS1 was demonstrated previously to be a potential therapeutic target for antiviral therapy by the identification of specific small-molecule inhibitors. One inhibitory compound, NSC125044, was subjected to chemical evaluation. Initial synthetic work comprised simplifying the core structure by removing unwanted functionality and determination of key features important for activity. Several subclasses of molecules were designed and synthesized to further probe activity and develop the basis for a structure activity relationship. Apparent potency, as judged by activity in virus replication assays, increased dramatically for some analogs, without cytotoxicity. Results suggest that the target binding site tolerates hydrophobic bulk as well as having a preference for weakly basic substituents.
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影响因子：
16
作者：
Nemeroff, ME;Barabino, SML;Krug, RM
通讯作者：
Krug, RM
影响因子：
5.4
作者：
Hayman, A.;Comely, S.;Barclay, W. S.
通讯作者：
Barclay, W. S.
影响因子：
--
作者：
Simonsen, L;Reichert, TA;Miller, MA
通讯作者：
Miller, MA
影响因子：
6.4
作者：
Nichol, Kristin L.;Treanor, John J.
通讯作者：
Treanor, John J.
DOI：
10.1073/pnas.0511120103
发表时间：
2006-02-21
影响因子：
11.1
作者：
Chen, H;Smith, GJD;Guan, Y
通讯作者：
Guan, Y