Abstract:
The plant-derived toxin ricin is classified as a type 2 ribosome-inactivating protein (RIP) and currently lacks effective clinical antidotes. The toxicity of ricin is mainly due to its ricin toxin A chain (RTA), which has become an important target for drug development. Previous studies have identified two essential binding pockets in the active site of RTA, but most existing inhibitors only target one of these pockets. In this study, we used computer-aided virtual screening to identify a compound called RSMI-29, which potentially interacts with both active pockets of RTA. We found that RSMI-29 can directly bind to RTA and effectively attenuate protein synthesis inhibition and rRNA depurination induced by RTA or ricin, thereby inhibiting their cytotoxic effects on cells in vitro. Moreover, RSMI-29 significantly reduced ricin-mediated damage to the liver, spleen, intestine, and lungs in mice, demonstrating its detoxification effect against ricin in vivo. RSMI-29 also exhibited excellent drug-like properties, featuring a typical structural moiety of known sulfonamides and barbiturates. These findings suggest that RSMI-29 is a novel small-molecule inhibitor that specifically targets ricin toxin A chain, providing a potential therapeutic option for ricin intoxication.
摘要:
植物衍生的毒素蓖麻毒素被归类为2型核糖体失活蛋白(RIP),目前缺乏有效的临床解毒剂。蓖麻毒素的毒性主要是由于其蓖麻毒素A链(RTA),成为药物开发的重要靶点。先前的研究已经确定了RTA活性位点中的两个必需结合袋,但是大多数现有的抑制剂只针对这些口袋中的一个。在这项研究中,我们使用计算机辅助虚拟筛查来鉴定一种名为RSMI-29的化合物,该化合物可能与RTA的两个活性口袋相互作用.我们发现RSMI-29可以直接与RTA结合,并有效减弱RTA或蓖麻毒素诱导的蛋白质合成抑制和rRNA脱嘌呤,从而在体外抑制它们对细胞的细胞毒性作用。此外,RSMI-29显著降低了蓖麻毒素介导的肝脏损伤,脾,脾肠,和小鼠的肺,证明其在体内对蓖麻毒素的解毒作用。RSMI-29还表现出优异的药物样特性,具有已知磺胺类和巴比妥酸盐的典型结构部分。这些发现表明,RSMI-29是一种新型的小分子抑制剂,特异性靶向蓖麻毒素A链,为蓖麻毒素中毒提供潜在的治疗选择。