SAR by MS: Discovery of a new class of RNA-binding small molecules for the hepatitis C virus: Internal ribosome entry site IIA subdomain
SAR by MS: Discovery of a new class of RNA-binding small molecules for the hepatitis C virus: Internal ribosome entry site IIA subdomain
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DOI：
10.1021/jm050815o
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发表时间：
2005-11-17
影响因子：
7.3
通讯作者：
Griffey, RH
中科院分区：
文献类型：
--
作者：
Seth, PP;Miyaji, A;Griffey, RH
报道了一类以亚微摩尔亲和力结合丙型肝炎病毒核糖核酸IRES IIA亚区的新型小分子。使用基于质谱学的筛选方法，从180000个成员的文库中鉴定出具有与结构域IIA的29聚核糖核酸模型类似的K-D的苯并咪唑‘HIT’1。进一步的MS辅助SAR(结构-活性关系)研究提供了与IIA RNA构建物具有亚微摩尔结合亲和力的苯并咪唑衍生物。优化后的苯并咪唑在细胞复制子实验中显示出活性，其浓度与其针对RNA靶标的K-D相当。
A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole 'hit' 1 with a K-D similar to 100 mu M to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure-activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their K-D for the RNA target.