Click Chemistry-Based Anthrax Lethal Factor Inhibitors

基于点击化学的炭疽致死因子抑制剂

• 批准号: 6851467
• 负责人: HARTMUTH C KOLB
• 金额: $ 23.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851467
• 关键词: Bacillus anthracis; anthrax; anthrax toxin; antibacterial agents; antibiotics; binding sites; bioterrorism /chemical warfare; chemistry; high throughput technology; liquid chromatography mass spectrometry; metalloendopeptidases; protein binding; technology /technique development

DESCRIPTION (provided by applicant): Anthrax is a potentially lethal disease, caused by Bacillus anthracis. It poses a significant threat as an agent of biological warfare and terrorism. Current therapy of anthrax is usually preventative, in form of a vaccine or, in case of acute infection, treatment with antibiotics. However, antibiotics alone typically fail against systemic anthrax unless administered at an early stage, since they do not neutralize the toxins produced by the bacterium. Consequently, there is a great need for small molecule toxin inhibitors. In combination with antibiotic therapy, such inhibitors could be life-saving. Of all three toxins produced by B. anthracis, we have chosen the Zinc proteinase 'lethal factor' (LF) as the target for inhibitor development, since it appears to be the critical virulence factor. In situ click chemistry, an exploratory new technique in which the target protein assembles its own inhibitors from simple precursors, will be employed for lead discovery and optimization. The main goals of the project are to (a) investigate the use of in situ click chemistry for the discovery and optimization of Anthrax LF inhibitors; (b) develop a detailed understanding of the structural requirements for LF inhibition, by structure-activity profiling and molecular modeling; (c) develop compounds that selectively inhibit Anthrax LF with high affinity (<1 mu M) and that are active in cell-based assays. Hits and leads will be optimized with the aid of target and cell-based inhibition assays, which will be accessed through collaborations. The specific aims are as follows: (1) Lead Discovery: Development of Anthrax LF inhibitors based on in situ click chemistry; (2) Lead Optimization: Optimization of binding affinity and cell-based activity.

描述（由申请人提供）：炭疽是一种潜在致命的疾病，由炭疽杆菌引起。作为生物战和恐怖主义的代理人，它构成了重大威胁。目前炭疽的治疗通常是预防性的，以疫苗的形式，或者在急性感染的情况下用抗生素治疗。然而，除非在早期阶段施用，否则单独使用抗生素通常无法对抗系统性炭疽，因为它们不能中和细菌产生的毒素。因此，非常需要小分子毒素抑制剂。与抗生素治疗相结合，此类抑制剂可以挽救生命。在炭疽杆菌产生的所有三种毒素中，我们选择锌蛋白酶“致死因子”(LF) 作为抑制剂开发的目标，因为它似乎是关键的毒力因子。原位点击化学是一种探索性新技术，其中靶蛋白从简单的前体组装自己的抑制剂，将用于先导化合物的发现和优化。该项目的主要目标是 (a) 研究使用原位点击化学来发现和优化炭疽 LF 抑制剂； (b) 通过结构-活性分析和分子建模，详细了解 LF 抑制的结构要求； (c) 开发以高亲和力（<1 μM）选择性抑制炭疽 LF 且在基于细胞的测定中具有活性的化合物。命中和先导化合物将借助靶点和基于细胞的抑制测定进行优化，这些测定将通过合作进行。具体目标如下：（1）先导化合物发现：基于原位点击化学开发炭疽LF抑制剂； (2) 先导化合物优化：结合亲和力和细胞活性的优化。