Jacobson Alan R, Adler Michael, Silvaggi Nicholas R, Allen Karen N, Smith Genessa M, Fredenburg Ross A, Stein Ross L, Park Jong-Beak, Feng Xiaochuan, Shoemaker Charles B, Deshpande Sharad S, Goodnough Michael C, Malizio Carl J, Johnson Eric A, Pellett Sabine, Tepp William H, Tzipori Saul
Absolute Science, Inc., Denver, CO, 80222, United States.
Neuroscience Branch, Medical Toxicology Division, USAMRICD, APG, MD, 21010, United States.
Toxicon. 2017 Oct;137:36-47. doi: 10.1016/j.toxicon.2017.06.016. Epub 2017 Jul 8.
Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.
肉毒杆菌神经毒素（BoNTs）是人类已知的毒性最强的物质，是神经麻痹性疾病肉毒中毒的病原体。它们易于生产且毒性极强，已导致这些神经毒素被列为一级生物恐怖主义威胁制剂，并促使人们持续努力开发应对生物恐怖袭击时中毒治疗的对策。虽然及时施用经批准的抗毒素可有效降低肉毒中毒的严重程度，但逆转中毒需要不同的策略。在本研究中，我们使用综合多测定方法评估了ABS 252和其他巯基乙酰胺小分子BoNT/A轻链活性位点抑制剂。ABS 252在酶促、基于细胞和肌肉活性测定中显示出抑制活性，重要的是，它使小鼠的死亡时间显著延迟。结果表明，多测定方法是发现潜在BoNT治疗候选物的有效策略。
