Functionalized dendrimers as endotoxin sponges.
Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. Polyamidoamine dendrimers, with the surface amines substoichiometrically derivatized with alkyl groups bind LPS with high affinity, neutralize LPS-induced inflammatory responses in vitro, and afford protection in a murine model of endotoxic shock. Dendrimers represent a new class of potentially useful compounds for the therapy of Gram-negative sepsis.
Cromer
Jens R
JR
Department of Medicinal Chemistry, University of Kansas, Life Sciences Research Laboratories, 1501 Wakarusa Drive, Lawrence, KS 66049, USA.
Wood
Stewart J
SJ
Miller
Kelly A
KA
Nguyen
Thuan
T
David
Sunil A
SA
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013499:Surface Properties
D004731:Endotoxins; D008070:Lipopolysaccharides; D011073:Polyamines; D009569:Nitric Oxide