David Sunil A, Sil Diptesh
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047, USA.
Subcell Biochem. 2010;53:255-83. doi: 10.1007/978-90-481-9078-2_12.
Sepsis, otherwise referred to as "blood poisoning" is a serious clinical problem, the incidence of which continues to rise in the US and worldwide despite advances in antimicrobial chemotherapy. The primary trigger in Gram-negative sepsis is endotoxin, a lipopolysaccharide (LPS) constituent of the outer membrane of all Gram-negative bacteria. The structurally highly conserved glycolipid called lipid A is the active moiety of LPS. Lipid A is composed of a hydrophilic, bis-phosphorylated di-glucosamine backbone, and a hydrophobic polyacyl domain. The bis-anionic, amphiphilic nature of lipid A enables it to interact with a variety of cationic hydrophobic ligands, including polymyxin B, a toxic peptide antibiotic which binds to lipid A and neutralizes endotoxicity. Having determined the structural basis of the interaction of polymyxin B with lipid A, our long-term goal has been to rationally design non-peptidic, nontoxic, small-molecule LPS-sequestrants. Our efforts began with defining the central pharmacophore that determined LPS-recognition and -neutralization properties in small molecules, which led to the discovery of a novel lipopolyamine lead, DS-96. DS-96 is an effective LPS-neutralizer, rivaling polymyxin B in a panel of vitro assays, as well as in protecting animals against endotoxicosis. Structure-activity relationships in our effort to rationally design endotoxin sequestering agents, preclinical assessment of hits and leads, and approaches to overcoming issues with toxicity are described in this chapter.
脓毒症，又称“败血症”，是一个严重的临床问题。尽管抗菌化疗取得了进展，但在美国和全球范围内，其发病率仍在持续上升。革兰氏阴性菌脓毒症的主要触发因素是内毒素，它是所有革兰氏阴性菌外膜的一种脂多糖（LPS）成分。结构上高度保守的糖脂脂质A是LPS的活性部分。脂质A由亲水性的双磷酸化二葡糖胺主链和疏水性的多酰基结构域组成。脂质A的双阴离子、两亲性质使其能够与多种阳离子疏水配体相互作用，包括多粘菌素B，一种有毒的肽类抗生素，它与脂质A结合并中和内毒素毒性。在确定了多粘菌素B与脂质A相互作用的结构基础后，我们的长期目标是合理设计非肽类、无毒的小分子LPS螯合剂。我们的工作始于确定决定小分子中LPS识别和中和特性的核心药效基团，这导致了一种新型脂多胺先导物DS-96的发现。DS-96是一种有效的LPS中和剂，在一系列体外试验中与多粘菌素B相当，并且在保护动物免受内毒素血症方面也表现出色。本章描述了我们在合理设计内毒素螯合剂过程中的构效关系、命中物和先导物的临床前评估以及克服毒性问题的方法。
