The pseudokinase-endoribonuclease RNase L plays important roles in antiviral innate immunity and is also implicated in many other cellular activities. The inhibition of RNase L showed therapeutic potential for Aicardi-Goutières syndrome (AGS). Thus, RNase L is a promising drug target. In this study, using an enzyme assay and NMR screening, we discovered 13 inhibitory fragments against RNase L. Cocrystal structures of RNase L separately complexed with two different fragments were determined in which both fragments bound to the ATP-binding pocket of the pseudokinase domain. Myricetin, vitexin, and hyperoside, three natural products sharing similar scaffolds with the fragment AC40357, demonstrated a potent inhibitory activity in vitro. In addition, myricetin has a promising cellular inhibitory activity. A cocrystal structure of RNase L with myricetin provided a structural basis for inhibitor design by allosterically modulating the ribonuclease activity. Our findings demonstrate that fragment screening can lead to the discovery of natural product inhibitors of RNase L.

中文翻译：

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通过基于片段的药物发现鉴定 RNase L 小分子抑制剂

假激酶核糖核酸内切酶 RNase L 在抗病毒先天免疫中发挥重要作用，并且还涉及许多其他细胞活动。RNase L 的抑制显示出治疗 Aicardi-Goutières 综合征 (AGS) 的潜力。因此，RNase L 是一个有前途的药物靶点。在本研究中，通过酶测定和 NMR 筛选，我们发现了 13 个针对 RNase L 的抑制片段。确定了分别与两个不同片段复合的 RNase L 的共晶结构，其中两个片段均与假激酶结构域的 ATP 结合袋结合。杨梅素、牡荆素和金丝桃苷这三种天然产物与片段 AC40357 具有相似的支架，在体外表现出有效的抑制活性。此外，杨梅素具有良好的细胞抑制活性。RNase L 与杨梅素的共晶结构通过变构调节核糖核酸酶活性为抑制剂设计提供了结构基础。我们的研究结果表明，片段筛选可以发现 RNase L 的天然产物抑制剂。