An RNA-targeted platform for anti-flavivirus drug discovery

总结 新出现和重新出现的蚊媒黄病毒引起广泛的死亡率、发病率和经济负担。预防和治疗蚊媒黄病毒的选择是有限的：黄病毒疫苗面临独特的开发挑战，没有抗病毒疗法，蚊子媒介已被证明难以根除。尽管有针对黄热病和日本脑炎病毒的疫苗，但这两种黄病毒每年共造成75，000多人死亡。世界上一半的人口面临登革热病毒（DENV）感染的风险，包括寨卡病毒在内的新出现的黄病毒对公共卫生构成重大挑战。 RNA是小分子药物发现的引人注目的靶标，并且RNA病毒（例如黄病毒）的基因组包含高度保守的可靶向结构。多种天然产物靶向核糖体RNA，建立了RNA作为药物靶点的概念证明;然而，RNA靶向药物发现仍然是一个新兴领域。DENV RNA基因组中的特定三级结构最近已被证明是病毒复制所必需的。这些结构在蚊媒黄病毒中高度保守，干扰它们的形成会抑制包装和复制，这表明破坏这些RNA基序的小分子将具有广谱抗黄病毒活性。 在Ribomestrium，我们的领先发现平台将非常快速和高通量的初始筛选与基于SHAPE技术的二次检测相结合，SHAPE技术是RNA结构分析的金标准。我们计划应用我们的平台来鉴定具有良好药物化学特性的小分子，这些小分子可以结合并破坏必需的DENV RNA基序的结构。这些先导化合物将作为2期项目中开发抗DENV和广谱抗黄病毒疗法的基础。 RNA具有广泛相似的总体特性，因此允许在单一情况下有效靶向RNA的策略可能允许靶向不同的治疗重要RNA。Ribome的长期愿景是应用这一平台技术来发现小分子治疗剂，这些小分子治疗剂靶向功能性RNA结构，这些结构涉及尚未批准的治疗方法。通过这项研究，我们将为RNA靶向配体发现的有效和通用方法建立原理证明。

SUMMARY Emerging and re-emerging mosquito-borne flaviviruses cause widespread mortality, morbidity, and economic burden. Options for prevention and treatment of mosquito-borne flaviviruses are limited: Flavivirus vaccines face unique development challenges, no antiviral therapies are available, and the mosquito vectors have proven difficult to eradicate. Despite vaccines against Yellow Fever and Japanese encephalitis viruses, these two flaviviruses together cause more than 75,000 deaths each year. Half of the world’s population is at risk of Dengue virus (DENV) infection, and emerging flaviviruses, including the Zika virus, pose significant public health challenges. RNA is a compelling target for small-molecule drug discovery, and the genomes of RNA viruses, such as flaviviruses, contain highly conserved targetable structures. Multiple natural products target ribosomal RNA, establishing proof of concept for RNA as a drug target; however, RNA-targeted drug discovery remains a nascent field. Specific tertiary structures in the DENV RNA genome have recently been shown to be essential for viral replication. These structures are highly conserved across mosquito-borne flaviviruses and interfering with their formation inhibits packaging and replication, suggesting that small molecules that disrupt these RNA motifs will have broad-spectrum antiflaviviral activity. At Ribometrix, our lead discovery platform combines a very rapid and high-throughput initial screen with a secondary assay based on SHAPE technology, the gold standard for RNA structure analyses. We plan to apply our platform to identify small molecules with favorable medicinal chemistry properties that bind to and disrupt the structure of essential DENV RNA motifs. These lead compounds will serve as the foundation for the development of anti-DENV and broad-spectrum antiflaviviral therapies in a Phase 2 project. RNAs share broadly similar overall properties, so a strategy that allows RNA to be targeted efficiently in a single case will likely allow targeting of diverse therapeutically important RNAs. The long-term vision of Ribometrix is to apply this platform technology to discover small-molecule therapeutics that target functional RNA structures involved in indications for which there are no approved therapies. With this study, we will establish proof-of-principle for an efficient and generic approach for RNA-targeted ligand discovery.