Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide

Thuan B. Nguyen, Ashok Kumar Adisechan, E. V K Suresh Kumar, Rajalakshmi Balakrishna, Matthew R. Kimbrell, Kelly A. Miller, Apurba Datta, Sunil A. David

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. The only therapeutic option aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide is Toraymyxin™, an extracorporeal hemoperfusion device using solid phase-immobilized polymyxin B (PMB). While PMB is known to effectively sequester LPS, its severe systemic toxicity proscribes its parenteral use, and hemoperfusion may not be feasible in patients in shock. In our continuing efforts to develop small-molecule mimics which display the LPS-sequestering properties, but not the toxicity of PMB, a series of mono- and bis-substituted dialkylpolyamines were synthesized and evaluated. We show that EVK-203, an alkylpolyamine compound, specifically binds to and neutralizes the activity of LPS, and affords complete protection in a murine model of endotoxic shock. EVK-203 is without any apparent toxicity when administered to mice at multiples of therapeutic doses for several days. The specific endotoxin-sequestering property along with a very favorable therapeutic index renders this compound an ideal candidate for preclinical development.

Original languageEnglish (US)
Pages (from-to)5694-5709
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number17
DOIs
StatePublished - Sep 1 2007

Bibliographical note

Funding Information:
This work was supported by NIH Grant 1R01 AI50107.

Keywords

  • Alkyl-polyamine
  • Endotoxin
  • Lipopolyamine
  • Lipopolysaccharide
  • Sepsis
  • Septic shock

Fingerprint

Dive into the research topics of 'Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide'. Together they form a unique fingerprint.

Cite this