Hydrophobic Polyamine Amides as Anti-Endotoxin Agents

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，在脓毒性休克的发病机制中起关键作用，脓毒性休克是全球死亡的主要原因，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）的发病机制。生物恐怖剂还涉及对LPS的有害宿主反应。开发治疗脓毒症的新治疗策略的一种可能的方法是隔离循环LPS，这是一种历史上使用针对LPS的结构保守的脂质区域的单克隆抗体解决的策略。然而，由于脂质上缺乏可接近的识别位点，使用单克隆抗体的一系列临床试验一直不成功。我们以前的工作，在各种蛋白质，肽和小分子中识别LPS的结合和中和所必需的结构的，导致了一类新的结构简单，无毒的分子，脂多胺，其结合和中和LPS在体外，并提供对LPS的攻击在两个革兰氏阴性脓毒症小鼠模型的保护。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，合成合理设计的新化合物库，以使结合亲和力和中和效力最大化，并显示出所需的药代动力学和毒理学特征。采用分级筛选策略，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的关键促炎介质产生的能力。将在两种革兰氏阴性脓毒症小鼠模型中进一步测试高活性分子。将在一组体外试验中系统地测定化合物的毒性。这些研究将用于生成预期IND提交的数据。

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.