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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action
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Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action

机译：四重配体对端粒酶抑制作用的重新评估及其作用机理

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摘要

Quadruplex ligands are often considered as telomerase inhibitors. Given the fact that some of these molecules are present in the clinical setting, it is important to establish the validity of this assertion. To analyze the effects of these compounds, we used a direct assay with telomerase-enriched extracts. The comparison of potent ligands from various chemical families revealed important differences in terms of effects on telomerase initiation and processivity. Although most quadruplex ligands may lock a quadruplex-prone sequence into a quadruplex structure that inhibits the initiation of elongation by telomerase, the analysis of telomerase-elongation steps revealed that only a few molecules interfered with the processivity of telomerase (i.e., inhibit elongation once one or more repeats have been incorporated). The demonstration that these molecules are actually more effective inhibitors of telomeric DNA amplification than extension by telomerase contributes to the already growing suspicion that quadruplex ligands are not simple telomerase inhibitors but, rather, constitute a different class of biologically active molecules. We also demonstrate that the popular telomeric repeat amplification protocol is completely inappropriate for the determination of telomerase inhibition by quadruplex ligands, even when PCR controls are included. As a consequence, the inhibitory effect of many quadruplex ligands has been overestimated.
机译：四重配体通常被认为是端粒酶抑制剂。考虑到某些分子存在于临床环境中的事实，重要的是要确定该断言的有效性。为了分析这些化合物的作用，我们对富含端粒酶的提取物进行了直接测定。来自各种化学家族的有效配体的比较揭示了在端粒酶引发和合成能力方面的重要差异。尽管大多数四链体配体可将四链体倾向序列锁定为四链体结构，从而抑制端粒酶引发的延伸，但对端粒酶延伸步骤的分析表明，只有少数分子干扰了端粒酶的合成能力（即一旦或更多的重复已被合并）。这些分子实际上是端粒DNA扩增比端粒酶延伸更有效的抑制剂的论据，导致人们越来越怀疑四重配体不是简单的端粒酶抑制剂，而是构成另一类生物活性分子。我们还证明了流行的端粒重复扩增方案对于四链体配体抑制端粒酶抑制作用是完全不合适的，即使包括PCR对照也是如此。结果，许多四重配体的抑制作用被高估了。

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