SYNTHESIS OF NEXT-GENERATION INHIBITORS OF BOTULINUM NEUROTOXIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肉毒杆菌神经毒素(BoNT)是肉毒杆菌产生的一种蛋白质，是世界上毒性最强的蛋白质。BONT的活性部位包括一个锌内肽酶，其结构已通过X射线结晶学确定。在这里，我们建议合成一个锌内肽酶亚单位的抑制剂文库。这些抑制剂的关键结构元素是2-或3-芳基吲哚。这些部分将使用PI实验室最近开发的氧化偶联技术来合成。对这些抑制剂的生物测试将在马萨诸塞大学达特茅斯大学肉毒杆菌中毒研究中心的合作者的实验室进行。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Botulinum neurotoxin (BoNT), a protein that is produced by Clostridium botulinum, is the most poisonous protein in the world. The active site of BoNT includes a zinc endopeptidase, whose structure has been elucidated by x-ray crystallography. Herein we propose to synthesize a library of inhibitors for the zinc endopeptidase subunit. The key structural element of these inhibitors is a 2- or 3-aryl indole. These moieties will be synthesized using oxidative coupling technology that has recently been developed in the PI's laboratory. Biological testing of the inhibitors will be performed in the laboratory of a collaborator at the Botulism Research Center at the University of Massachusetts-Dartmouth.