Development of small-molecule endotoxin sequestering agents.
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.
David
Sunil A
SA
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047, USA. sdavid@ku.edu
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Diptesh
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002236:Carbohydrate Conformation; D002986:Clinical Trials as Topic; D004731:Endotoxins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013096:Spermine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C534982:DS-96 compound; D004731:Endotoxins; D008070:Lipopolysaccharides; D011073:Polyamines; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; D013096:Spermine; D009569:Nitric Oxide