发现含 YTH 结构域 m6A RNA 阅读器的新抑制剂

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chuan-Hui Wang and Huiqing Zhou
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引用次数: 0

摘要

N6-甲基腺苷(m6A)是哺乳动物 mRNA 中的一种丰富修饰,主要通过 "阅读器 "蛋白的特异性识别在基因表达中发挥重要的调控功能。YTH 家族蛋白是已知 m6A 阅读器的一个主要家族,它们通过 YTH 结构域特异性地识别经 m6A 修饰的转录本。尽管 YTH-m6A 识别在生物学和疾病中具有重要意义,但很少有小分子抑制剂能特异性地扰乱这种相互作用。在此,我们报告了通过筛选针对 YTHDF1 蛋白 YTH 结构域的核苷类似物文库,发现了一种新的 YTH-m6A RNA 识别抑制剂("N-7")。N-7 在体外对人类 YTHDF1、YTHDF2、YTHDF3、YTHDC1 和 YTHDC2 蛋白的五个 YTH 结构域具有泛抑制作用,通过荧光偏振竞争试验测定的 IC50 范围在 30-48 μM 之间。我们通过热转移试验证明了 N-7 与 YTH 结构域蛋白的直接相互作用。N-7 拓展了含 m6A YTH 结构域的阅读器抑制剂的化学结构图,并促进了未来针对外转录组的阅读器功能研究和治疗工作的抑制剂开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of a new inhibitor for YTH domain-containing m6A RNA readers†

Discovery of a new inhibitor for YTH domain-containing m6A RNA readers†

N 6-methyladenosine (m6A) is an abundant modification in mammalian mRNAs and plays important regulatory roles in gene expression, primarily mediated through specific recognition by “reader” proteins. YTH family proteins are one major family of known m6A readers, which specifically recognize m6A-modified transcripts via the YTH domains. Despite the significant relevance of YTH-m6A recognition in biology and diseases, few small molecule inhibitors are available for specifically perturbing this interaction. Here we report the discovery of a new inhibitor (“N-7”) for YTH-m6A RNA recognition, from the screening of a nucleoside analogue library against the YTH domain of the YTHDF1 protein. N-7 is characterized to be a pan-inhibitor in vitro against five YTH domains from human YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 proteins, with IC50 values in the range of 30–48 μM measured using a fluorescence polarization competition assay. We demonstrated that N-7 directly interacts with the YTH domain proteins via a thermal shift assay. N-7 expands the chemical structure landscape of the m6A YTH domain-containing reader inhibitors and potentiates future inhibitor development for reader functional studies and therapeutic efforts in targeting the epitranscriptome.

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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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