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Heparin derivatives for the targeting of multiple activities in the inflammatory response.

Veraldi, N; Hughes, AJ; Rudd, TR; Thomas, HB; Edwards, SW; Hadfield, L; Skidmore, MA; Siligardi, G; Cosentino, C; Shute, JK; Naggi, A; Yates, EA

Authors

N Veraldi

AJ Hughes

TR Rudd

HB Thomas

SW Edwards

L Hadfield

G Siligardi

C Cosentino

JK Shute

A Naggi

EA Yates



Abstract

An attractive strategy for ameliorating symptoms arising from the multi-faceted processes of excessive and/or continual inflammation would be to identify compounds able to interfere with multiple effectors of inflammation. The well-tolerated pharmaceutical, heparin, is capable of acting through several proteins in the inflammatory cascade, but its use is prevented by strong anticoagulant activity. Derivatives of heparin involving the periodate cleavage of 2,3 vicinal diols in non-sulfated uronate residues (glycol-split) and replacement of N-sulphamido- with N-acetamido- groups in glucosamine residues, capable of inhibiting neutrophil elastase activity in vitro, while exhibiting attenuated anticoagulant properties, have been identified and characterised. These also interact with two other important modulators of the inflammatory response, IL-8 and TNF-alpha. It is therefore feasible in principle to modulate several activities, while minimising anticoagulant side effects, providing a platform from which improved anti-inflammatory agents might be developed.

Acceptance Date Sep 22, 2014
Publication Date Mar 6, 2015
Journal Carbohydr Polym
Print ISSN 0144-8617
Publisher Elsevier
Pages 400 - 407
DOI https://doi.org/10.1016/j.carbpol.2014.09.079
Keywords Neutrophil elastase, IL-8, TNF-alpha, Inflammatory network, Chemically modified heparin, Glycol-split
Publisher URL http://www.sciencedirect.com/science/article/pii/S0144861714009898

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