Development and testing of anthrax toxin inhibitors

炭疽毒素抑制剂的开发和测试

• 批准号: 6874924
• 负责人: JEREMY S MOGRIDGE
• 金额: $ 115.6万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874924
• 关键词: anthrax; anthrax toxin; bacterial antigens; bacterial proteins; bacterial toxins; cooperative study; drug screening /evaluation; gel filtration chromatography; inhibitor /antagonist; laboratory mouse; laboratory rat; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; peptides; pharmacokinetics; tissue /cell culture

DESCRIPTION (provided by applicant): The objective of our research proposal is to develop inhibitors of anthrax toxin that prevent the death of animals challenged with Bacillus anthracis spores. Anthrax toxin is a combination of three non-toxic proteins that are secreted separately by the bacterium and then assemble into toxic complexes on the mammalian cell surface. The protective antigen component of the toxin binds the anthrax toxin receptor and oligomerizes into heptamers that bind the toxic enzymes, edema factor and lethal factor. Inhibitors of anthrax toxin that block either toxin assembly or cytosolic delivery of the enzymatic proteins are expected to be effective anthrax therapeutics because the toxin is necessary for disease progression and causes death of the patient. We have previously synthesized a molecule consisting of multiple copies of a toxin-binding peptide coupled to a polymer backbone. The peptide alone can prevent the assembly of the tripartite toxin in vitro and its polyvalent display by the backbone increases its effective activity. We demonstrated that this inhibitor prevents the activity of anthrax toxin in rats, indicating that this molecule is a promising lead compound for an anthrax therapeutic. During the period of this proposal, we will test whether this inhibitor can prevent death of mice challenged with Bacillus anthracis spores. We will also assess the inhibitor's toxicity and pharmacokinetics. In addition to testing this lead compound, we will synthesize and test derivatives to develop a mature compound. The first class of molecules we synthesize will display inhibitory peptides from a variety a polymeric backbones and nanoparticles, which will be chosen for properties such as biocompatibility and bioavailability. The second class of molecules will consist of backbones of defined molecular weight that display multiple copies of the inhibitory peptide. We will also optimize the sequence of the peptide to increase its inhibitory activity. Reiterative design and pharmacological testing will facilitate the development of inhibitors with high potency, long lifetime, and low toxicity. These inhibitors may be an effective adjunct to antibiotic therapy in the treatment of anthrax.

描述（由申请人提供）：我们研究提案的目的是开发炭疽毒素抑制剂，以防止炭疽芽孢杆菌孢子攻击动物的死亡。炭疽毒素是三种无毒蛋白质的组合，它们分别由细菌分泌，然后在哺乳动物细胞表面组装成有毒复合物。毒素的保护性抗原成分结合炭疽毒素受体并寡聚成结合毒性酶、水肿因子和致死因子的七聚体。阻断毒素组装或酶蛋白质的胞质递送的炭疽毒素抑制剂预期是有效的炭疽治疗剂，因为毒素是疾病进展所必需的并导致患者死亡。 我们先前已经合成了一种分子，由多个拷贝的毒素结合肽偶联到一个聚合物骨架组成。单独的肽可以防止三重毒素在体外的组装，并且其通过主链的多价展示增加了其有效活性。我们证明了这种抑制剂可以阻止大鼠中炭疽毒素的活性，表明这种分子是一种有前途的炭疽治疗药物的先导化合物。在本提案期间，我们将测试这种抑制剂是否可以预防炭疽芽孢杆菌孢子攻击小鼠的死亡。我们还将评估抑制剂的毒性和药代动力学。 除了测试这种先导化合物，我们还将合成和测试衍生物，以开发一种成熟的化合物。我们合成的第一类分子将展示来自各种聚合物骨架和纳米颗粒的抑制肽，这些分子将根据生物相容性和生物利用度等特性进行选择。第二类分子将由显示抑制肽的多个拷贝的确定分子量的主链组成。我们还将优化肽的序列以增加其抑制活性。重复设计和药理学测试将有助于开发具有高效力、长寿命和低毒性的抑制剂。这些抑制剂可能是治疗炭疽的抗生素治疗的有效辅助手段。