Hydrophobic Polyamine Amides as Anti-Endotoxin Agents

描述(申请人提供)：内毒素是革兰氏阴性细菌的外膜成分，在感染性休克的发病机制中起着关键作用，感染性休克是全球范围内的主要死亡原因，目前尚无有效的治疗方法。对A类(Francisella Tularensis)和B类(Brucella spp.)生物恐怖主义制剂还涉及有害的宿主对内毒素的反应。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内毒素，这一策略历来是使用针对脂多糖结构保守的脂类区域的单抗来解决的。然而，由于脂质上缺乏可识别的位点，一系列使用单抗的临床试验都未获成功。我们之前的工作是在各种蛋白质、多肽和小分子中确定结合和中和内毒素所必需的结构条件，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内毒素，并在两种革兰氏阴性脓毒症小鼠模型中提供对抗内毒素攻击的保护。在与MediQuest治疗公司的合作下，我们建议基于我们已经建立的脂多胺的最佳结构模板，合成合理设计的新化合物文库，以最大限度地提高结合亲和力和中和效力，并展示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内毒素的相互作用。测试化合物将被筛选为能够抑制内毒素诱导的细胞激活和感染性休克的关键促炎介质的产生。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。这些化合物的毒性将在一组体外测试中系统地进行测定。这些研究将有助于为预期的IND提交生成数据。

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.