title: Development of small-molecule endotoxin sequestering agents.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047, USA. sdavid@ku.edu
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
authors.forename: Diptesh
authors.initials: D
authors.lastname: Sil
mesh_terms: 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
chemical_list: 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