E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide targets abrin and ricin toxicity: Hitting two toxins with one stone
E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide targets abrin and ricin toxicity: Hitting two toxins with one stone
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DOI：
10.1016/j.biopha.2021.112134
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发表时间：
2021-08-31
影响因子：
7.5
通讯作者：
Saxena，Nandita
中科院分区：
文献类型：
--
作者：
Phatak，Pooja;Chauhan，Vinita;Saxena，Nandita
小分子抑制剂（SMI）对滋贺毒素的酶活性的效力促使评价它们对相关毒素即蓖麻毒素和相思豆毒素的效力。蓖麻毒素与滋贺毒素一样，被列为B类生物武器，属于核糖体失活蛋白（RIP）的II型家族。蓖麻毒素虽然在结构和功能上与蓖麻毒素相似，但毒性更大。本研究用A549细胞进行了35个化合物的体外抗相思豆毒蛋白和蓖麻毒蛋白的活性测定，其中5个化合物对相思豆毒蛋白和2个化合物对蓖麻毒蛋白具有保护作用，IC_（50）值分别为30.5-1379 μM和300-341 μM。这些发现通过基于荧光的热位移测定得到证实。此外，通过表面等离子体共振分析和体外蛋白质合成分析证实了有希望的化合物与毒素组分的结合。体内研究显示，化合物4 E-N-（2-乙酰基-苯基）-3-苯基-丙烯酰胺对口服致死剂量的相思豆毒素和蓖麻毒素具有完全的保护作用。因此，本研究提出了E-N-（2-乙酰基-苯基）-3-苯基-丙烯酰胺作为对抗RIP的先导化合物的出现。
The efficacy of small molecule inhibitors (SMIs) against the enzymatic activity of Shiga toxin prompted the evaluation of their efficacy on related toxins viz. ricin and abrin. Ricin, like Shiga toxin, is listed as a category B bioweapon and belongs to the type II family of ribosome inactivating proteins (RIPs). Abrin though structurally and functionally similar to ricin, is considerably more toxic. In the present study, 35 compounds were evaluated in A549 cells inin vitroassays, of which 5 offered protection against abrin and 2 against ricin, with IC50values ranging between 30.5-1379 μM and 300-341 μM, respectively. These findings are substantiated by fluorescence based thermal shift assay. Moreover, the binding of the promising compounds to the toxin components has been validated by Surface Plasmon Resonance assay and in vitro protein synthesis assay.In vivostudies reveal complete protection of mice with compound 4 E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide against orally administered lethal doses of, both, abrin and ricin. The present study thus proposes the emergence of E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide as a lead compound against RIPs.