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J Biol Chem, Vol. 273, Issue 22, 13563-13569, May 29, 1998
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From the Protease inhibition by secretory leukocyte
protease inhibitor (SLPI) is accelerated by the sulfated
polysaccharides. The nature of the SLPI-polysaccharide interaction,
explored with affinity chromatography, indicated that this interaction
was sensitive to the charge and type of polysaccharide. Dextran and
chondroitin had the lowest affinity for SLPI, followed by dermatan,
heparan, and dextran sulfates. While heparin bound SLPI tightly, the
highest affinity heparin chains unexpectedly contained a lower level of sulfation than more weakly interacting chains. Heparin
oligosaccharides, prepared using heparin lyase I were SLPI-affinity
fractionated. Surprisingly, undersulfated heparin oligosaccharides
bound SLPI with the highest affinity, suggesting the importance of free
hydroxyl groups for high affinity interaction. Isothermal titration
calorimetry was used to determine the thermodynamics of SLPI
interaction with a low molecular weight heparin, an undersulfated
decasaccharide and a tetrasaccharide. The studies showed 12-14
saccharide units, corresponding to molecular weight of ~4,800, were
required for a 1:1 (SLPI:heparin) binding stoichiometry. Furthermore,
an undersulfated decasaccharide was able to bind SLPI tightly
(Kd ~13 nM), resulting in its
activation and the inhibition of neutrophil elastase and pancreatic
chymotrypsin. The in vitro assessment of heparin and the
decasaccharide and tetrasaccharide using stopped-flow kinetics
suggested that heparin was the optimal choice to study SLPI-based
in vivo protease inhibition. SLPI and heparin were co-administered by inhalation in therapy against antigen-induced airway
hyperresponsiveness in a sheep bronchoprovocation model. Heparin, in
combination with SLPI demonstrated in vivo efficacy reducing early and late phase bronchoconstriction. Heparin also increased the therapeutic activity of SLPI against antigen-induced airway hyperresponsiveness.
Division of Medicinal and Natural Products
Chemistry, Amgen Inc., Boulder, Colorado 80301, and the ** University of
Miami School of Medicine, Miami Beach, Florida 33140
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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