title: Heparin derivatives for the targeting of multiple activities in the inflammatory response.
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.
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni", Milano 20133, Italy. Electronic address: noemi.veraldi@gmail.com.
authors.forename: Noemi
authors.initials: N
authors.lastname: Veraldi
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK; Diamond Light Source Ltd., Harwell Innovation Campus, Didcot OX11 8DE, Oxfordshire, UK. Electronic address: A.Hughes2@liverpool.ac.uk.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Hughes
authors.affiliation: Diamond Light Source Ltd., Harwell Innovation Campus, Didcot OX11 8DE, Oxfordshire, UK. Electronic address: timothy.rudd@diamond.ac.uk.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rudd
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Electronic address: H.B.Thomas@liverpool.ac.uk.
authors.forename: Huw B
authors.initials: HB
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Electronic address: s.w.edwards@liv.ac.uk.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Edwards
authors.affiliation: School of Life Sciences, Keele University, Keele ST5 5BG, Staffordshire, UK. Electronic address: l.hadfield@keele.ac.uk.
authors.forename: Lynsay
authors.initials: L
authors.lastname: Hadfield
authors.affiliation: School of Life Sciences, Keele University, Keele ST5 5BG, Staffordshire, UK; Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Electronic address: m.a.skidmore@biol.keele.ac.uk.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Skidmore
authors.affiliation: Diamond Light Source Ltd., Harwell Innovation Campus, Didcot OX11 8DE, Oxfordshire, UK; Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Electronic address: giuliano.siligardi@diamond.ac.uk.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Siligardi
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni", Milano 20133, Italy. Electronic address: cosentino@ronzoni.it.
authors.forename: Cesare
authors.initials: C
authors.lastname: Cosentino
authors.affiliation: Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK. Electronic address: jan.shute@port.ac.uk.
authors.forename: Janis K
authors.initials: JK
authors.lastname: Shute
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni", Milano 20133, Italy. Electronic address: naggi@ronzoni.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Naggi
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK. Electronic address: eayates@liv.ac.uk.
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Yates
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D016209:Interleukin-8 / Q000032:analysis; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D016209:Interleukin-8; D053491:Proteinase Inhibitory Proteins, Secretory; D006493:Heparin; D019272:Leukocyte Elastase
keywords: Chemically modified heparin; Glycol-split; IL-8; Inflammatory network; Neutrophil elastase; TNF-alpha