Heparan sulfate-protein interactions--a concept for drug design?
The glycosaminoglycan, heparan sulfate (HS) is composed of alternating units of hexuronic acid and glucosamine, that are variously sulfate-substituted at different positions. Proteoglycans carrying HS chains are ubiquitously expressed at cell surfaces and in the extracellular matrix. The structures of these chains are highly variable, yet under strict biosynthetic control. Due to their high negative charge, HS chains interact with a multitude of proteins, including growth factors/morphogens and their receptors, chemokines, and extracellular-matrix proteins. These interactions regulate key events in embryonic development and in homeostasis. HS-protein interactions vary with regard to specificity, and often seem to depend primarily on charge density rather than on strict carbohydrate sequence. The organization of sulfated domains along the HS chain appears to be of importance. HS-protein interactions are involved in a variety of pathophysiological processes, including inflammation, angiogenesis, and amyloid deposition. Drugs targeting such interactions may be useful in treatment of disease conditions as diverse as cancer, inflammatory bowel disease, and Alzheimer's disease. Potential drugs may mimick HS oligosaccharides, but could also be peptides blocking the protein-binding domains of HS chains. Drug generation requires a firm understanding of the pathophysiological role of a given HS-protein interaction, and of the aspect of specificity. Even inhibition of HS biosynthesis may be considered.
Lindahl
Ulf
U
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden. ulf.lindahl@imbim.uu.se
D000990:Antithrombin III / Q000378:metabolism; D001665:Binding Sites; D004194:Disease / Q000209:etiology; D016503:Drug Delivery Systems; D015195:Drug Design; D004358:Drug Therapy; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*
D000990:Antithrombin III; D006497:Heparan Sulfate; D011506:Proteins