Diversity-oriented chemical modification of heparin: Identification of charge-reduced N-acyl heparin derivatives having increased selectivity for heparin-binding proteins.
The diversity-oriented chemical modification of heparin is shown to afford charge-reduced heparin derivatives that possess increased selectivity for binding heparin-binding proteins. Variable N-desulfonation of heparin was employed to afford heparin fractions possessing varied levels of free amine. These N-desulfonated heparin fractions were selectively N-acylated with structurally diverse carboxylic acids using a parallel synthesis protocol to generate a library of 133 heparin-derived structures. Screening library members to compare affinity for heparin-binding proteins revealed unique heparin-derived structures possessing increased affinity and selectivity for individual heparin-binding proteins. Moreover, N-sulfo groups in heparin previously shown to be required for heparin to bind specific proteins have been replaced with structurally diverse non-anionic moieties to afford identification of charge-reduced heparin derivatives that bind these proteins with equivalent or increased affinity compared to unmodified heparin. The methods described here outline a process that we feel will be applicable to the systematic chemical modification of natural polyanionic polysaccharides and the preparation of synthetic oligosaccharides to identify charge-reduced high affinity ligands for heparin-binding proteins.
Huang
Liusheng
L
Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Kerns
Robert J
RJ
D000215:Acylation; D000588:Amines / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D006493:Heparin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D006860:Hydrogen Bonding; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000588:Amines; D011506:Proteins; D006493:Heparin