竞争性微阵列筛选揭示了 DHX15 RNA G-四倍体的功能配体

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-02 DOI:10.1021/acsmedchemlett.3c00574

Peri R. Prestwood, Mo Yang, Grace V. Lewis, Sumirtha Balaratnam, Kamyar Yazdani and John S. Schneekloth Jr.*,

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引用次数: 0

摘要

越来越多的人认为 RNA 是有价值的治疗靶点，因此开发鉴定和验证 RNA 靶点和配体的方法比以往任何时候都更加重要。在这里，我们利用生物信息学方法鉴定了 DHX15 mRNA 的 5′ 非翻译区 (5′ UTR) 中含有发夹的 RNA G-四链体 (rG4)。通过使用一种新型竞争性小分子微阵列（SMM）方法，我们发现了一种能与 DHX15 rG4 特异性结合的化合物（KD = 12.6 ± 1.0 μM）。该 rG4 直接影响体外 DHX15 报告 mRNA 的翻译，而我们的化合物（F1）与该结构的结合可抑制高达 57% 的翻译（IC50 = 22.9 ± 3.8 μM）。这种方法使我们能够识别并靶向一种与癌症相关的、没有已知抑制剂的螺旋酶的 mRNA。我们的靶点识别方法和筛选方法的新颖性使我们的工作为未来开发针对 RNA 靶点的新型小分子癌症疗法提供了信息。

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Competitive Microarray Screening Reveals Functional Ligands for the DHX15 RNA G-Quadruplex

RNAs are increasingly considered valuable therapeutic targets, and the development of methods to identify and validate both RNA targets and ligands is more important than ever. Here, we utilized a bioinformatic approach to identify a hairpin-containing RNA G-quadruplex (rG4) in the 5′ untranslated region (5′ UTR) of DHX15 mRNA. By using a novel competitive small molecule microarray (SMM) approach, we identified a compound that specifically binds to the DHX15 rG4 (K_D = 12.6 ± 1.0 μM). This rG4 directly impacts translation of a DHX15 reporter mRNA in vitro, and binding of our compound (F1) to the structure inhibits translation up to 57% (IC₅₀ = 22.9 ± 3.8 μM). This methodology allowed us to identify and target the mRNA of a cancer-relevant helicase with no known inhibitors. Our target identification method and the novelty of our screening approach make our work informative for future development of novel small molecule cancer therapeutics for RNA targets.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.