Nonnucleoside inhibitor of measles virus RNA-Dependent RNA polymerase complex activity
Nonnucleoside inhibitor of measles virus RNA-Dependent RNA polymerase complex activity
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DOI：
10.1128/aac.00289-07
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发表时间：
2007-07-01
影响因子：
4.9
通讯作者：
Plemper, Richard K.
中科院分区：
文献类型：
--
作者：
White, Laura K.;Yoon, Jeong-Joong;Plemper, Richard K.
副粘病毒包括几种主要的人类病原体。虽然减毒活疫苗可以预防副粘病毒家族的成员麻疹病毒，但该病毒仍然是全球死亡的主要原因，每年造成约2100万例病例和30万至40万人死亡。因此，非常需要开发新的抗病毒药物，以改善严重麻疹的病例管理并使病毒暴发保持沉默。我们之前已经描述了新型MV融合抑制剂的发展。该领域中预先存在的或新出现的耐药性的可能性构成了鉴定具有不同靶标的其他MV抑制剂的基本原理。在这里，我们报告了一种基于细胞的高通量筛选MV抗病毒药物的方法的开发和实施，该方法已经产生了几个热门候选药物。经过二次化验和化学合成的证实，最有效的HIT被发现是一种靶向特异性的MV复制抑制因子，具有理想的药物性质。事实证明，该化合物对目前在世界各地流行的不同MV基因型的多个初级分离物具有高度的活性，显示出35至145 NM的有效浓度。值得注意的是，它不干扰病毒进入，并且与MV融合抑制物类缺乏交叉耐药性。亚感染水平的机制表征表明，该化合物代表了MV RNA依赖的RNA聚合酶复合体活性的一流非核苷抑制剂。单独或与融合抑制剂联合使用，这类新化合物具有很高的开发潜力，可以作为一种有效的治疗MV的药物，并可能进一步描述病毒聚合酶复合体的机制。
Paramyxoviruses comprise several major human pathogens. Although a live-attenuated vaccine protects against measles virus (MV), a member of the paramyxovirus family, the virus remains a principal cause of worldwide mortality and accounts for approximately 21 million cases and 300,000 to 400,000 deaths annually. The development of novel antivirals that allow improved case management of severe measles and silence viral outbreaks is thus highly desirable. We have previously described the development of novel MV fusion inhibitors. The potential for preexisting or emerging resistance in the field constitutes the rationale for the identification of additional MV inhibitors with a diverse target spectrum. Here, we report the development and implementation of a cell-based assay for high-throughput screening of MV antivirals, which has yielded several hit candidates. Following confirmation by secondary assays and chemical synthesis, the most potent hit was found to act as a target-specific inhibitor of MV replication with desirable drug-like properties. The compound proved highly active against multiple primary isolates of diverse MV genotypes currently circulating worldwide, showing active concentrations of 35 to 145 nM. Significantly, it does not interfere with viral entry and lacks cross-resistance with the MV fusion inhibitor class. Mechanistic characterization on a subinfection level revealed that the compound represents a first-in-class nonnucleoside inhibitor of MV RNA-dependent RNA polymerase complex activity. Singly or in combination with the fusion inhibitors, this novel compound class has high developmental potential as a potent therapeutic against MV and will likely further the mechanistic characterization of the viral polymerase complex.