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，在感染性休克的发病机制中起关键作用，感染性休克是世界范围内死亡的主要原因，迄今尚无有效治疗方法。某些A类（土拉弗朗西斯菌）和B类（布鲁氏菌）生物恐怖制剂的发病机制也涉及有害宿主对LPS的反应。开发治疗败血症的新治疗策略的一种可能方法是隔离循环LPS，这一策略历来使用针对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，使用单克隆抗体进行的一系列临床试验均未成功。我们之前的工作是在多种蛋白质、多肽和小分子中确定结合和中和LPS所需的结构条件，从而鉴定出一类结构简单、无毒的新型分子，脂多胺，它在体外结合和中和LPS，并在两种革兰氏阴性脓毒症小鼠模型中提供对LPS攻击的保护。在与MediQuest Therapeutics公司的合作中，我们建议合成合理设计的新化合物文库，以最大化结合亲和力和中和效力，并显示理想的药代动力学和毒理学特征，基于我们已经用脂多胺建立的最佳结构模板。采用分层筛选策略，这些分子与LPS的相互作用将被全面评估。测试化合物将筛选抑制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脓毒症小鼠模型中进一步测试。化合物的毒性将在一组体外试验中系统地确定。这些研究将为预期的新药申报提供数据。

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.