Discovery of a TNF-alpha antagonist using chondroitin sulfate microarrays.
We report the first example of synthetic chondroitin sulfate (CS) microarrays to rapidly identify glycosaminoglycan-protein interactions and probe the specificity of proteins for distinct sulfation sequences. Using the microarrays, we identify a novel interaction between CS and TNF-alpha, a proinflammatory cytokine involved in rheumatoid arthritis, Crohn's disease, and psoriasis. Moreover, we demonstrate that CS-E tetrasaccharides and polysaccharides enriched in the CS-E sulfation motif can inhibit the activity of this therapeutically important cytokine. We anticipate that carbohydrate microarrays will accelerate our understanding of glycosaminoglycan-protein interactions and the role of sulfation in modulating physiological and disease states.
Tully
Sarah E
SE
Division of Chemistry and Chemical Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA.
Rawat
Manish
M
Hsieh-Wilson
Linda C
LC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D040081:Protein Array Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D020298:U937 Cells / Q000187:drug effects
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D002809:Chondroitin Sulfates