Inhibitors of slit protein interactions with the heparan sulphate proteoglycan glypican-1: potential agents for the treatment of spinal cord injury.
1. The heparan sulphate proteoglycan glypican-1 is a major high-affinity ligand of the Slit proteins. 2. Messenger RNA for both Slit-2 and glypican-1 is strongly upregulated and coexpressed in the reactive astrocytes of injured adult brain, suggesting a possible function of Slit proteins and glypican-1 in the adult central nervous system as significant components of the inhibitory environment that prevents axonal regeneration after injury. 3. Based on the hypothesis that adverse effects on axonal regeneration may be due to a glypican-Slit complex or the retention of glypican-binding C-terminal proteolytic processing fragments of Slit at the injury site, we used ELISA to examine a number of small molecules and low molecular weight heparin analogues for their ability to inhibit glypican-Slit interactions. 4. Our studies have led to the identification of several potent inhibitors with a favourable therapeutic profile that can now be tested in a spinal cord injury model. Among the most promising of these are a low molecular weight heparin produced by periodate oxidation and having no significant anticoagulant activity, the chemically sulphonated yeast-derived phosphomannan PI-88 and a number of randomly derivatized water-soluble sulphated dextrans.
Department of Pharmacology, New York University Medical Center, New York, New York 10016, USA.
Elizabeth
E
Lau
Richard U
RU
Margolis
D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry; D017985:Dalteparin / Q000737:chemistry; D016264:Dextran Sulfate / Q000737:chemistry; D015195:Drug Design; D017984:Enoxaparin / Q000737:chemistry; D000077425:Fondaparinux; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D053673:Glypicans / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D009844:Oligosaccharides; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D010504:Periodic Acid / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D000098552:Slit Homolog 2 Protein
D000925:Anticoagulants; D017984:Enoxaparin; D006023:Glycoproteins; D053673:Glypicans; D006495:Heparin, Low-Molecular-Weight; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D009844:Oligosaccharides; D011134:Polysaccharides; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C120158:phosphomannopentaose sulfate; C120566:slit protein, vertebrate; D010504:Periodic Acid; D016264:Dextran Sulfate; C009288:metaperiodate; D000077425:Fondaparinux; D000098552:Slit Homolog 2 Protein; D017985:Dalteparin