Inhibition of therapeutically important polymerases with high affinity bis-intercalators.
Inhibition of therapeutically important polymerases with high affinity bis-intercalators.
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DOI：
10.1016/j.bmcl.2012.05.041
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发表时间：
2012-07-15
影响因子：
2.7
通讯作者：
Friedman, Simon H.
中科院分区：
文献类型：
--
作者：
Jain, Nitin;Francis, Subhashree;Friedman, Simon H.
我们之前已经证明，端粒酶等聚合酶可以被靶向关键 RNA/DNA 双链体底物的分子（例如嵌入剂）抑制。在这项工作中，我们证明这也适用于逆转录酶，并表明可以对先导嵌入剂进行修饰以提高抑制功效。具体来说，我们使用多个同时嵌入的策略，通过使用可变链接器连接两个嵌入器。这种设计背后的基本原理是特定的接头有可能增加目标双链体的亲和力和特异性。我们合成了 45 个乙锭双嵌入剂库，其中嵌入剂之间的距离有系统地变化。我们观察到，相对于单体先导化合物，二聚体文库的成员具有改善的端粒酶和逆转录酶抑制作用。我们表明，当检测混合物中抑制剂结合的非生产性位点受到限制时，这种相对于单嵌入剂的抑制改进最为显着。完成此操作后，观察到抑制功效增加了 400 倍。
We have previously demonstrated that polymerases such as telomerase can be inhibited by molecules (e.g., intercalators) that target the key RNA/DNA duplex substrate. In this work we show that this also holds true for reverse transcriptase, and show that the lead intercalators can be modified to increase inhibition efficacy. Specifically, we use the strategy of multiple simultaneous intercalation, by linking two intercalators with a variable linker. The rationale behind this design is that a specific linker has the potential to increase affinity and specificity for the target duplex. We have synthesized a library of 45 ethidium bis-intercalators in which the distance between intercalators is systematically varied. We observe that members of the dimer library have improved telomerase and reverse transcriptase inhibition, relative to the monomeric leads. We show that this improvement in inhibition over mono-intercalators is most prominent when non-productive sites of inhibitor binding are limited in the assay mix. When this is done, a 400-fold increase in inhibition efficacy is observed.
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影响因子：
5.1
作者：
Francis, R;West, C;Friedman, SH
通讯作者：
Friedman, SH
影响因子：
2.9
作者：
Szatmari, I;Tokés, S;Aradi, J
通讯作者：
Aradi, J
影响因子：
2.7
作者：
West, C;Francis, R;Friedman, SH
通讯作者：
Friedman, SH
影响因子：
2.9
作者：
Ren, JS;Chaires, JB
通讯作者：
Chaires, JB
影响因子：
2.7
作者：
Rangarajan, Subhashree;Friedman, Simon H.
通讯作者：
Friedman, Simon H.