Development of small-molecule endotoxin sequestering agents

Sunil A. David, Diptesh Sil

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 sep- sis 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 struc- tural 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 ratio- nally design endotoxin sequestering agents, preclinical assessment of hits and leads, and approaches to overcoming issues with toxicity are described in this chapter.

Original languageEnglish (US)
Pages (from-to)255-283
Number of pages29
JournalSub-cellular biochemistry
Volume53
DOIs
StatePublished - Jan 1 2010

Keywords

  • Alkylpolyamine
  • Cytokine
  • Endotoxin
  • Lipopolyamine
  • Lipopolysaccharide
  • P38MAPK
  • Pharmacodynamics
  • Pharmacokinetics
  • Polymyxin B
  • Prodrug
  • Sepsis
  • Septic shock

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