Abstract
The tetrasaccharide sequence of heparin oligosaccharides is the minimum chain length possessing anti-allergic activity, as the disaccharide fraction is inactive. Since sulfation pattern can modify the biological actions of heparin, we hypothesized that "supersulfation" of the inactive heparin disaccharide could confer anti-allergic activity to this molecule. To test this, we produced a supersulfated heparin disaccharide (Hep-SSD) and evaluated its anti-allergic activity in sheep with documented antigen-induced early and late airway responses (EAR and LAR) and airway hyperresponsiveness (AHR). Porcine intestinal heparin was depolymerized with nitrous acid, the disaccharide fraction separated by size exclusion chromatography, and then treated with pyridine-sulfur trioxide complex to yield Hep-SSD. Its chemical structure [IdoU2',3',4'S (1→4) AMan1,3,6S] was confirmed by HPLC, Mass Spectrometry and NMR analysis. Inhaled doses of 5 mg, 10 mg and 20 mg Hep-SSD produced inhibition of EAR (8%, 35% and 35%), LAR (50%, 80%, and 77%) and AHR (67%, 100% and 75%), respectively. A single oral dose of 2 mg/kg Hep-SSD given 90 min before challenge significantly inhibited EAR, LAR and AHR, but 1 mg/kg was ineffective. Multi dose oral treatment ...Continue Reading
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