Hydrophobic Polyamine Amides as Anti-Endotoxin Agents

作为抗内毒素剂的疏水性聚胺酰胺

• 批准号: 7069972
• 负责人: Sunil A David
• 金额: $ 27.07万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-20 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069972
• 关键词: amides; antibiotics; chemical binding; clinical research; combinatorial chemistry; cooperative study; drug discovery /isolation; gram negative bacteria; human subject; interleukin 1; laboratory mouse; lipopolysaccharides; nitric oxide; pharmacokinetics; polyamines; septic shock; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Lipopolysaccharides (LPS) or endotoxins are outer membrane constituents of gram-negative bacteria that play a key role in the pathogenesis of septic shock, a leading cause of mortality worldwide for which there is as yet no effective therapy. The pathogenesis of certain Category A (Francisella tularensis) and Category B (Brucella spp.) bioterrorism agents also involves deleterious host responses to LPS. One possible approach to developing novel therapeutic strategies to treat sepsis is to sequester circulating LPS, a strategy that has been historically addressed using monoclonal antibodies directed against the structurally conserved lipid regions of LPS. However, a series of clinical trials using monoclonal antibodies have been unsuccessful owing to the lack of accessible recognition sites on the lipid. Our previous work on identifying structural requisites necessary for binding and neutralization of LPS in a variety of proteins, peptides and small molecules led to the identification of a novel class of structurally simple, nontoxic molecules, the lipopolyamines, which bind and neutralize LPS in vitro, and afford protection against LPS challenge in two murine models of gram-negative sepsis. In collaboration with MediQuest Therapeutics, Inc., we propose to synthesize libraries of novel compounds rationally designed to maximize binding affinity and neutralization potency, and to exhibit desirable pharmacokinetic and toxicological profiles, based on optimal structural templates that we have already established with the lipopolyamines. Employing a hierarchical screening strategy, the interactions of these molecules with LPS will be comprehensively evaluated. Test compounds will be screened for the ability to inhibit LPS-induced cellular activation and production of key proinflammatory mediators of septic shock. Highly active molecules will be further tested in two murine models of gram-negative sepsis. The toxicity of the compounds will be systematically determined in a panel of in vitro assays. These studies will serve to generate data for anticipated IND submissions.

描述（由申请人提供）：脂多糖（LPS）或内毒素是革兰氏阴性菌的外膜成分，在败血性休克的发病机制中发挥着关键作用，败血性休克是全世界死亡的主要原因，目前尚无有效的治疗方法。某些 A 类（土拉弗朗西斯菌）和 B 类（布鲁氏菌属）生物恐怖主义制剂的发病机制还涉及宿主对 LPS 的有害反应。开发治疗脓毒症的新治疗策略的一种可能方法是隔离循环 LPS，该策略历史上一直使用针对 LPS 结构保守的脂质区域的单克隆抗体来解决。然而，由于脂质上缺乏可接近的识别位点，一系列使用单克隆抗体的临床试验均未成功。我们之前的工作是确定各种蛋白质、肽和小分子中脂多糖结合和中和所必需的结构要求，从而鉴定出一类结构简单、无毒的新型分子，即脂多胺，它可以在体外结合和中和脂多糖，并在两种革兰氏阴性败血症小鼠模型中提供针对 LPS 攻击的保护作用。与 MediQuest Therapeutics, Inc. 合作，我们建议基于我们已经用脂多胺建立的最佳结构模板，合成合理设计的新型化合物库，以最大限度地提高结合亲和力和中和效力，并表现出理想的药代动力学和毒理学特征。采用分层筛选策略，将全面评估这些分子与 LPS 的相互作用。将筛选测试化合物抑制 LPS 诱导的细胞活化和脓毒性休克关键促炎介质产生的能力。高活性分子将在两种革兰氏阴性败血症小鼠模型中进行进一步测试。这些化合物的毒性将在一组体外测定中系统地确定。这些研究将为预期的 IND 提交生成数据。