Botulinum Toxin - Small Molecular Weight BoNT Inhibitors

肉毒杆菌毒素 - 小分子量 BoNT 抑制剂

• 批准号: 7558743
• 负责人: HARTMUTH C KOLB
• 金额: $ 22.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7558743
• 关键词: Active Sites; Acute; Affinity; Antitoxins; Binding; Biological; Biological Availability; Botulinum Toxins; Botulism; Cells; Cessation of life; Chemistry; Clostridium botulinum; Computer Assisted; Enzymes; Goals; Libraries; Life; Ligands; Measures; Metalloproteases; Metals; Molecular Weight; Neurotoxins; Object Attachment; Onset of illness; Paralysed; Peptides; Pharmaceutical Chemistry; Procedures; Research Institute; Serotyping; Specificity; Structure; Toxin; Work; X-Ray Crystallography; Zinc; analog; base; combinatorial; combinatorial chemistry; computerized tools; design; experience; hydroxamate; improved; inhibitor/antagonist; molecular modeling; peptidomimetics; predictive modeling; prevent; scaffold; small molecule; trend

The neurotoxins produced by Clostridium botulinum are among the most potent toxins known, leading to life threatening acute flaccid paralysis. Current measures for treating botulism are all limited to macromolecular antitoxins, which must be administered at the onset of the disease to prevent long-term damage or death. Hence, there is a great need for cell-permeable small molecules that inhibit these bacterial metalloproteinases, which may find use as biological weapons. The goal of this proposal is to identify small molecular weight BoNT inhibitors with broad spectrum activity against the various subtypes, and possibly even the various serotypes. Our structure-guided combinatorial chemistry approach encompasses the following key features: (a) Structure-based design of combinatorial libraries of'divalent' molecules that may bind to the enzyme's active site through a substrate-like fragment and a metal-coordinating group, (b) designing substrate mimics by replacing peptide bonds with click chemistry-derived linkages, and (c) applying medicinal chemistry principles to increase the chances for improved bioavailability. The specific aims are as follows: (1) Design and produce several hydroxamate-based libraries that are targeted against BoNT metalloproteinases; (2) Design and produce several libraries of peptidomimetic compounds that contain heterocyclic Zinc ligands; (3) Develop predictive computational tools for binding-affinity and targetspecificity trends.

肉毒梭菌产生的神经毒素是已知的最有效的毒素之一，导致生命 威胁性急性脆性瘫痪。治疗肉毒杆菌的当前措施都限于大分子 抗毒素，必须在疾病发作时进行给药，以防止长期损害或死亡。 因此，非常需要细胞可渗透的小分子，这些分子抑制这些细菌 金属蛋白酶，可能会发现用作生物武器。该提议的目的是确定小 分子量重的BONT抑制剂具有宽光谱活性的各种亚型，并且可能 甚至各种血清型。我们的结构引导的组合化学方法包括 以下关键特征：（a）基于结构的'数量分子组合库的设计 通过底物样片段和金属配位基团结合酶的活性位点，（b） 通过点击化学衍生的链接替换肽键来设计底物模仿，并且（c） 应用药物化学原则，以增加提高生物利用度的机会。具体 目的如下：（1）设计和生产几个基于羟氨酸的库，这些图书馆针对 BONT金属蛋白酶； （2）设计并生产几个肽含量化合物的库 包含杂环锌配体； （3）开发用于结合 - 亲属和目标特定性的预测计算工具 趋势。