E-N-(2-acetyl-phenyl)-3-phenyl-acrylamide targets abrin and ricin toxicity: Hitting two toxins with one stone - 09/10/21
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Abstract |
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 in in vitro assays, of which 5 offered protection against abrin and 2 against ricin, with IC50 values 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 vivo studies 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.
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Highlights |
• | Abrin and ricin are type II ribosome inactivating proteins isolated from plants. |
• | They are listed as potent biological/chemical warfare agents devoid of a commercially available antidote. |
• | Thirty-five small molecule inhibitors were screened for their antidotal activity, targeting catalytic site of theses RIPs. |
• | The SMIs were evaluated for their efficacy by in silico, in vitro and in vivo assays. |
• | E-N-(2-acetyl-phenyl)-3-phehylacrylamide completely protected mice against lethal doses of abrin and ricin. |
Abbreviations : CC50, CDC, FTSA, IC50, i.p., IVTS, Ka, KD, LDH, MTD, MTT, NR, RIPs, SI, SMI, SPR, SRL, Stx
Keywords : Abrin, Ricin, Shiga toxin, Small molecule inhibitor, Ribosome inactivating proteins (RIPs)
Plan
Vol 143
Article 112134- novembre 2021 Retour au numéro
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