Engineered bio-active polysaccharides from heparin.
[Image: see text] Heparin, the well-known anticoagulant polysaccharide, is also active in many other biological systems owing to its structural similarity to HS, but usually lacks selectivity because it is more highly sulfated. A series of straightforward chemical reactions (de-O-sulfation, de-N-sulfation and re-N-acetylation), carried out to partial or complete extent, were combined, resulting in a number of modified heparin polysaccharide derivatives with altered properties. These exhibited a range of abilities to promote cell signalling through the FGF/FGFR tyrosine kinase signalling system, in an in vitro cell assay with combinations of FGF-1, -2, -3 and FGFR 1 and 3. One polysaccharide (N-acetylated, 6-O- and 2-O-sulfated heparin), with only a fraction (<10(-3)) of the anticoagulant activity of heparin (200 U . mg(-1)), promoted FGF-2-mediated angiogenesis (10-fold) and therefore had an improved ratio of pro-angiogenic activity to anticoagulant activity in excess of 10(4) compared to heparin. These results demonstrate that heparin-derived polysaccharides can be engineered for selected activities and have potential in a wide range of medical, biotechnological and tissue-engineering applications. Effect of selected engineered heparin polysaccharides on angiogenesis.
Guimond
Scott E
SE
School of Biological Sciences, University of Liverpool, L69 7ZB, UK.
Turnbull
Jeremy E
JE
Yates
Edwin A
EA
D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D011134:Polysaccharides / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects
D000925:Anticoagulants; D011134:Polysaccharides; D005346:Fibroblast Growth Factors; D006493:Heparin