Small Molecule Inhibitors of C. perfringens Epsilon-Toxin

产气荚膜梭菌 Epsilon 毒​​素的小分子抑制剂

• 批准号: 7653817
• 负责人: VLADIMIR A KARGINOV
• 金额: $ 35.35万
• 依托单位: INNOVATIVE BIOLOGICS, INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653817
• 关键词: Affinity; Bacterial Toxins; Biological; Biological Assay; Categories; Cells; Clinical Research; Clostridium perfringens; Clostridium perfringens epsilon toxin; Cyclodextrins; Data; Development; Domestic Animals; Drug Kinetics; Enterotoxemia; Feasibility Studies; Goals; Intoxication; Lead; Libraries; Mediating; Mus; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Small Business Innovation Research Grant; Testing; Therapeutic; Toxic effect; Toxin; base; beta-Cyclodextrins; betadex; biodefense; cytotoxic; cytotoxicity; design; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; innovation; novel strategies; pre-clinical; public health relevance; small molecule; therapeutic development; weapons

DESCRIPTION (provided by applicant): C. perfringens epsilon-toxin (ETX) is a potential biological weapon included in the list of category B priority agents. The overall goal of this proposal is to identify and perform in vivo testing of new inhibitors of ETX using a novel approach for the inactivation of pore-forming toxins developed at Innovative Biologics, Inc. It is based on the blocking of the target pore with molecules having the same symmetry as the pore itself. Results from our SBIR Phase I project demonstrated that beta-cyclodextrin derivatives designed to block the transmembrane channel formed by epsilon-toxin can inhibit its cytotoxicity at low micromolar concentrations. Based on the successful completion of this feasibility study, we propose to design, synthesize and screen a library of beta-cyclodextrin derivatives for inhibitors of epsilon-toxin's activity and test selected lead compounds in mice. The specific aims of this Phase II study are: (1) Optimize the assay for testing the ability of beta-cyclodextrin derivatives to inhibit the cytotoxic activity of C. perfringens epsilon-toxin. (2) Utilize initial testing data in concert with pharmaceutical chemistry to design and synthesize a biased library of beta- cyclodextrin derivatives with an enhanced affinity to the epsilon-toxin pore. (3) Screen the library using the cell-based assay to select the most potent inhibitors and test their ability to block the pore formed by ETX. (4) Perform toxicity, pharmacokinetic and efficacy tests in mice challenged with epsilon-toxin using at least three compounds to select in vivo validated leads. In the long-term, subsequent pre-clinical and clinical studies will lead to the development of a new drug against C. perfringens epsilon-toxin. PUBLIC HEALTH RELEVANCE: Epsilon toxin produced by Clostridium perfringens is one of the most lethal bacterial toxins. It is regarded as a potential biological weapon and is included in the list of category B priority agents. Currently, there is no effective treatment for the 5-toxin-mediated intoxication; therefore, a great need exists for the development of therapeutics against this biodefense toxin.

描述（由申请人提供）：C。产气荚膜杆菌ε毒素（ETX）是列入B类优先物剂清单的一种潜在生物武器。本提案的总体目标是使用Innovative Biologics，Inc.开发的用于灭活成孔毒素的新方法，鉴定并进行新ETX抑制剂的体内试验。它基于用具有与孔本身相同对称性的分子阻塞目标孔。我们SBIR I期项目的结果表明，设计用于阻断ε毒素形成的跨膜通道的β-环糊精衍生物可以在低微摩尔浓度下抑制其细胞毒性。在成功完成本可行性研究的基础上，我们建议设计、合成和筛选用于抑制ε毒素活性的β-环糊精衍生物库，并在小鼠中测试所选的先导化合物。本II期研究的具体目的是：（1）优化β-环糊精衍生物抑制C.产气荚膜杆菌ε毒素。(2)与药物化学一起利用初始测试数据来设计和合成对ε-毒素孔具有增强的亲和力的β-环糊精衍生物的偏向文库。(3)使用基于细胞的测定筛选文库以选择最有效的抑制剂并测试其阻断ETX形成的孔的能力。(4)使用至少三种化合物在用ε毒素激发的小鼠中进行毒性、药代动力学和功效测试，以选择体内验证的先导化合物。从长远来看，后续的临床前和临床研究将导致抗C.产气荚膜杆菌ε毒素。与公共卫生的关系：产气荚膜梭菌产生的埃帕霉素毒素是最致命的细菌毒素之一。它被视为一种潜在的生物武器，被列入B类优先物剂清单。目前，还没有针对5-毒素介导的中毒的有效治疗;因此，非常需要开发针对这种生物防御毒素的治疗剂。