Development and testing of anthrax toxin inhibitors

炭疽毒素抑制剂的开发和测试

• 批准号: 7046921
• 负责人: JEREMY S MOGRIDGE
• 金额: $ 116.23万
• 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/7046921
• 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(申请人提供)：我们研究提案的目标是开发炭疽毒素的抑制剂，以防止受到炭疽芽胞杆菌孢子挑战的动物死亡。炭疽毒素是由细菌单独分泌的三种无毒蛋白质的组合，然后在哺乳动物细胞表面组装成有毒的复合体。毒素的保护性抗原成分与炭疽毒素受体结合，并寡聚成七聚体，结合毒酶、水肿因子和致死因子。炭疽毒素的抑制剂可以阻止毒素组装或酶蛋白的胞液递送，预计将是有效的炭疽治疗药物，因为这种毒素是疾病发展所必需的，并导致患者死亡。 我们之前已经合成了一个由多个副本的毒素结合肽偶联到聚合物主干上的分子。单肽可以阻止三方毒素在体外的组装，其骨架的多价展示增加了其有效活性。我们证明了这种抑制物可以抑制炭疽毒素在大鼠体内的活性，这表明该分子是一种很有前途的炭疽治疗先导化合物。在这项提议期间，我们将测试这种抑制剂是否可以防止炭疽芽胞攻击的小鼠死亡。我们还将评估该抑制剂的毒性和药代动力学。除了测试这种先导化合物外，我们还将合成和测试衍生物，以开发出成熟的化合物。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性多肽，它们将被选作生物兼容性和生物利用度等性质的选择。第二类分子将由分子质量确定的骨架组成，显示多个抑制性多肽副本。我们还将优化多肽的序列，以提高其抑制活性。重复设计和药理试验将有助于开发高效、长寿命、低毒的抑制剂。在炭疽病的治疗中，这些抑制剂可能是抗生素治疗的有效辅助药物。