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Therapeutic targeting of HCV internal ribosomal entry site RNA.

机译：HCV内部核糖体进入部位RNA的治疗靶向。

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摘要

HCV infection is a significant human disease, leading to liver cirrhosis and cancer, and killing >10,000 people in the US annually. Translation of the viral RNA genome is initiated by ribosomal binding to a highly structured RNA element, the internal ribosomal entry site (IRES), which presents a novel target for therapeutic intervention. We will first discuss studies of oligonucleotide therapeutics targeting various regions of the 340-nucleotide IRES, many of which have effectively blocked IRES function in vitro and are active against virus replication in cell culture. Although low nanomolar potencies have been obtained for DNA- and RNA-based molecules, stability and drug delivery challenges remain to be addressed for these particular HCV compounds. Several classes of small molecule inhibitors have been identified from screening protocols or designed from established RNA therapeutic scaffolds. In particular, small molecule IRES inhibitors based on a benzimidazole scaffold bind specifically to the IRES, and inhibit viral replication in cell culture at micromolar concentrations with low toxicity. The structure of the RNA target in complex with a representative member of these small molecule inhibitors demonstrates that a large RNA conformational change occurs upon inhibitor binding. The RNA complex shows how the inhibitor alters the global RNA structure and provides a framework for structure-based drug design of novel HCV therapeutics.
机译：HCV感染是一种重要人类疾病，导致肝硬化和癌症，每年在美国杀死> 10,000人。病毒RNA基因组的翻译通过核糖体结合与高度结构化的RNA元素，内部核糖体进入部位（IRES）引发，这提出了一种用于治疗干预的新靶标。我们将首先探讨靶向340核苷酸异构的各个区域的寡核苷酸治疗剂的研究，其中许多在体外有效地阻断了IRES功能，并对细胞培养中的病毒复制有效。虽然已经获得了低纳摩尔疗效，但是对于基于DNA和RNA的分子，仍然可以针对这些特定的HCV化合物寻址稳定性和药物递送挑战。已经从筛选方案中鉴定出几种类别的小分子抑制剂或由已建立的RNA治疗支架设计。特别地，基于苯并咪唑支架的小分子IRES抑制剂特异性地结合在IRE中，并在具有低毒性的微摩尔浓度下抑制细胞培养中的病毒复制。与这些小分子抑制剂的代表性成员复合物中RNA靶的结构表明，在抑制剂结合时发生大的RNA构象变化。 RNA复合物展示了抑制剂如何改变全局RNA结构，并为新的HCV治疗剂提供基于结构的药物设计框架。

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