TY - JOUR
T1 - Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide
AU - Nguyen, Thuan B.
AU - Adisechan, Ashok Kumar
AU - Suresh Kumar, E. V K
AU - Balakrishna, Rajalakshmi
AU - Kimbrell, Matthew R.
AU - Miller, Kelly A.
AU - Datta, Apurba
AU - David, Sunil A.
N1 - Funding Information:
This work was supported by NIH Grant 1R01 AI50107.
PY - 2007/9/1
Y1 - 2007/9/1
N2 - 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.
AB - 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.
KW - Alkyl-polyamine
KW - Endotoxin
KW - Lipopolyamine
KW - Lipopolysaccharide
KW - Sepsis
KW - Septic shock
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U2 - 10.1016/j.bmc.2007.06.015
DO - 10.1016/j.bmc.2007.06.015
M3 - Article
C2 - 17583517
AN - SCOPUS:34447260517
SN - 0968-0896
VL - 15
SP - 5694
EP - 5709
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 17
ER -