Ricin toxin A subunit (RTA) is the catalytic subunit of ricin, which depurinates an adenine from the sarcin/ricin loop in eukaryotic ribosomes. There are no approved inhibitors against ricin. We used a new strategy to disrupt RTA–ribosome interactions by fragment screening using surface plasmon resonance. Here, using a structure-guided approach, we improved the affinity and inhibitory activity of small-molecular-weight lead compounds and obtained improved compounds with over an order of magnitude higher efficiency. Four advanced compounds were characterized by X-ray crystallography. They bind at the RTA–ribosome binding site as the original compound but in a distinctive manner. These inhibitors bind remotely from the catalytic site and cause local conformational changes with no alteration of the catalytic site geometry. Yet they inhibit depurination by ricin holotoxin and inhibit the cytotoxicity of ricin in mammalian cells. They are the first agents that protect against ricin holotoxin by acting directly on RTA.

中文翻译：

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使用基于片段的方法和基于结构的设计合成和结构表征靶向核糖体结合的蓖麻毒素抑制剂

蓖麻毒素 A 亚基 (RTA) 是蓖麻毒素的催化亚基，可从真核生物核糖体中的肌氨酸/蓖麻毒素环中去除腺嘌呤。没有批准的蓖麻毒蛋白抑制剂。我们使用了一种新的策略，通过使用表面等离子体共振的片段筛选来破坏 RTA-核糖体的相互作用。在这里，我们使用结构引导的方法提高了小分子量先导化合物的亲和力和抑制活性，并获得了效率提高一个数量级的改进化合物。四种先进的化合物通过 X 射线晶体学表征。它们作为原始化合物在 RTA-核糖体结合位点结合，但以独特的方式结合。这些抑制剂从催化位点远程结合并导致局部构象变化而催化位点几何形状没有改变。然而，它们抑制蓖麻毒素全毒素的脱嘌呤并抑制哺乳动物细胞中蓖麻毒素的细胞毒性。它们是第一个通过直接作用于 RTA 来预防蓖麻毒素全毒素的药物。