Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide.
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.
Nguyen
Thuan B
TB
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Lawrence, KS 66047, USA.
Adisechan
Ashok Kumar
AK
Suresh Kumar
E V K
EV
Balakrishna
Rajalakshmi
R
Kimbrell
Matthew R
MR
Miller
Kelly A
KA
Datta
Apurba
A
David
Sunil A
SA
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
D016207:Cytokines; C523024:EVK-203; D008070:Lipopolysaccharides; D011073:Polyamines