Conformational constraint as a means for understanding RNA-aminoglycoside specificity
Conformational constraint as a means for understanding RNA-aminoglycoside specificity
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DOI：
10.1021/ja050918w
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发表时间：
2005-07-13
影响因子：
15
通讯作者：
Tor, Y
中科院分区：
文献类型：
--
作者：
Blount, KF;Zhao, F;Tor, Y
氨基糖苷类抗生素缺乏高的RNA靶选择性，这是由它们的静电驱动结合模式和它们的构象适应性造成的。其糖苷键周围的固有灵活性使它们能够轻松地呈现各种构象，从而使它们能够在结构上适应不同的RNA靶标。这种结构混杂导致形成具有不同RNA靶标的氨基糖苷类复合物，其中抗生素呈现不同的构象。这种差异表明，共价连接氨基糖苷类中的各个环可以减少其可用的构象，从而改变靶点选择性。为了探索这种可能性，构象约束的新霉素和巴龙霉素类似物，旨在模拟A-位点结合的氨基糖苷类结构已被合成和它们的亲和力的TAR和A-位点，两个治疗相关的RNA目标，已被评估。根据设计，该限制对与A位点结合的有害影响最小。然而，令人惊讶的是，将这些新霉素类抗生素预组织成TAR不利的结构对与该HIV-1 RNA序列的结合没有有害影响。我们合理化这些观察表明，A-网站和HIV TAR具有固有的不同选择性对氨基糖苷类。TAR RNA的固有可塑性，加上构象约束类似物内的剩余灵活性，使该RNA位点成为这种聚阳离子配体的适应性靶点。相比之下，深度包封的A位点是更具鉴别力的RNA靶标。这些观察结果表明，未来设计新的靶标选择性基于RNA的治疗剂将不得不考虑RNA靶标的固有“结构”选择性，而不仅仅是低分子量配体显示的选择性模式。
The lack of high RNA target selectivity displayed by aminoglycoside antibiotics results from both their electrostatically driven binding mode and their conformational adaptability. The inherent flexibility around their glycosidic bonds allows them to easily assume a variety of conformations, permitting them to structurally adapt to diverse RNA targets. This structural promiscuity results in the formation of aminoglycoside complexes with diverse RNA targets in which the antibiotics assume distinct conformations. Such differences suggest that covalently linking individual rings in an aminoglycoside could reduce its available conformations, thereby altering target selectivity. To explore this possibility, conformationally constrained neomycin and paromomycin analogues designed to mimic the A-site bound aminoglycoside structure have been synthesized and their affinities to the TAR and A-site, two therapeutically relevant RNA targets, have been evaluated. As per design, this constraint has minimal deleterious effect on binding to the A-site. Surprisingly, however, preorganizing these neomycin-class antibiotics into a TAR-disfavored structure has no deleterious effect on binding to this HIV-1 RNA sequence. We rationalize these observations by suggesting that the A-site and HIV TAR possess inherently different selectivities toward aminoglycosides. The inherent plasticity of the TAR RNA, coupled to the remaining flexibility within the conformationally constrained analogues, makes this RNA site an accommodating target for such polycationic ligands. In contrast, the deeply encapsulating A-site is a more discriminating RNA target, These observations suggest that future design of novel target selective RNA-based therapeutics will have to consider the inherent "structural" selectivity of the RNA target and not only the selectivity patterns displayed by the low molecular weight ligands.