High-throughput screening-based identification of paramyxovirus inhibitors
High-throughput screening-based identification of paramyxovirus inhibitors
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DOI：
10.1177/1087057108321089
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Plemper, Richard K.
中科院分区：
文献类型：
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作者：
Yoon, Jeong-Joong;Chawla, Dhruv;Plemper, Richard K.
副粘病毒家族的几个成员构成了主要的人类病原体，其共同导致了世界范围内的主要发病率和死亡率。为了开发抗麻疹病毒（MV）（副粘病毒家族的重要成员）的新疗法，作者报道了一种高通量筛选方案，其使用非重组原代MV毒株作为靶。分析的实施已经从137，500个条目的库中产生了60个命中候选者。反筛选和剂量反应曲线的生成将该池缩小到35种化合物，活性浓度为500。库挖掘的结构类似物的几个确认的命中结合重新测试确定的候选人揭示了高精度的主要命中识别。其中11种确认的命中干扰病毒进入，而其余24种化合物靶向病毒生命周期的试验后步骤。针对副粘病毒家族的选定成员的活性测试揭示了3种活性：1）仅MV特异性阻断剂，2）MV和相同属的相关病毒的抑制剂，和3）具有针对不同副粘病毒亚科属的活性的更宽范围的抑制剂。最后一类的代表可能会开辟途径，通过打击铅化学的发展广泛的副粘病毒抑制剂。
Several members of the paramyxovirus family constitute major human pathogens that, collectively, are responsible for major morbidity and mortality worldwide. in an effort to develop novel therapeutics against measles virus (MV), a prominent member of the paramyxovirus family, the authors report a high-throughput screening protocol that uses a nonrecombinant primary MV strain as targets. Implementation of the assays has yielded 60 hit candidates from a 137,500-entry library. Counterscreening and generation of dose-response curves narrows this pool to 35 compounds with active concentrations 500. Library mining for structural analogs of several confirmed hits combined with retesting of identified candidates reveals a high accuracy of primary hit identification. Eleven of the confirmed hits interfere with viral entry, whereas the remaining 24 compounds target postentry steps of the viral life cycle. Activity testing against selected members of the paramyxovirus family reveals 3 paaterns of activity: 1) exclusively MV-specific blockers, 2) inhibitors of MV and relates viruses of the same genus, and 3) broader range inhibitors with activity against a different Paramyxovirinae genus. Representatives of the last class may open avenues for the development of broad-range paramyxovirus inhibitors through hit-to-lead chemistry.