PMID: 8608324Jan 1, 1994Paper

Inhibition of lipopolysaccharide-induced TNF-alpha production by semisynthetic polymyxin-B conjugated dextran

Biotechnology Therapeutics
C P CoyneB W Fenwick

Abstract

During episode of severe endotoxemia, concentrations of both lipopolysaccharide and its lipid A-core subfraction are liberated from gram-negative bacteria and become elevated within the systemic circulation. Lipid-A core is the most homogeneous and physiologically toxic segment of the lipopolysaccharide molecule. Polymyxin-B has profound binding avidity for the lipid A-core subfraction of lipopolysaccharide. The mechanism of this binding avidity involves the development of attractive forces between the cationic groups of polymyxin-B and the anionic groups of the lipid A-core moiety of lipopolysaccharide. Complementary attractive forces include hydrophobic interactions which additionally become established between the octylheptanoyl group of polymyxin-B and the saturated carbon chains of the lipid A-core moiety. This paper describes a method for the semisynthetic production of polymyxin-B conjugated dextran in the form of polymyxin-B.ABH.dextran applying the photoreactive crosslinking reagent azidobenzoyl hydrazide (ABH). Molecular design and development of a semisynthetic technique for the conjugation of polymyxin-B to purified dextran fractions was motivated by the pronounced nephrotoxicity associated with this cationic polype...Continue Reading

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