Modified RNAs as potential drug targets
Modified RNAs as potential drug targets
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DOI：
10.18388/abp.1998_4281
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发表时间：
1998-01-01
影响因子：
1.7
通讯作者：
Agris, PF
中科院分区：
文献类型：
--
作者：
Guenther, R;Forrest, B;Agris, PF
博来霉素（BLM）是一种天然抗生素，可有效治疗选定的癌症。虽然博来霉素的确切治疗机制尚不清楚，但其靶点被认为是核酸。除了切割DNA外，在体外，Fe-博来霉素特异性地切割酵母tRNA的反密码子（Phe）。使用CD和荧光光谱，我们已经发现，脱辅基博莱霉素结合到酵母tRNA（苯丙氨酸）的反密码子的合成RNA类似物的亲和力类似于以前报道的DNA。为了理解BLM的选择性，应该解释镁离子在RNA识别中的作用。Fe-BLM的许多RNA底物，包括酵母tRNA（苯丙氨酸），不裂解的药物时，Mg 2+浓度超过1 mM。竞争实验与反密码子类似物提供洞察的作用，镁离子在RNA识别BLM。这些简单的修饰RNA可能是有用的模型系统，研究BLM/RNA识别和开发高选择性药物对RNA的目标。
Bleomycin (BLM) is a natural antibiotic that is effective in treatment of selected cancers. Although the exact therapeutic mechanism of bleomycin is not known, its target is thought to be a nucleic acid. Besides cleaving DNA, in vitro, Fe-bleomycin cleaves the anticodon of yeast tRNA(Phe) specifically. Using CD and fluorescence spectroscopy we have found that apo-bleomycin binds to synthetic RNA analogs of the anticodon of yeast tRNA(Phe) with an affinity similar to that previously reported for DNA. In order to understand BLM's selectivity, the role magnesium ions play in RNA recognition should be explained. Many RNA substrates for Fe-BLM, including yeast tRNA(Phe), are not cleaved by the drug when the Mg2+ concentration exceeds 1 mM. Competition experiments with anticodon analogs provide insight into the role of magnesium ions in RNA recognition by BLM. These simple modified RNAs may be useful as model systems for investigating BLM/RNA recognition and development of highly selective drugs toward RNA targets.