SYNTHESIS OF NEW ALPHA-THIOSIALODENDRIMERS AND THEIR BINDING-PROPERTIES TO THE SIALIC-ACID SPECIFIC LECTIN FROM LIMAX-FLAVUS

Carbohydrate-protein binding interactions can be greatly amplified usi ng the cluster or multivalent effect. In previous studies, sialylated multibranched L-lysine dendrimers were found to be patent inhibitors o f the hemagglutination of human erythrocytes by Influenza viruses. In order to further the understanding of multivalency and its role in car bohydrate-protein interactions, glycoconjugates with differing carbohy drate densities, conformations, and interglycosidic spacings must be p repared. The synthesis and biological testing of structurally similar divergent and tethered alpha-sialodendrimers are presented herein. alp ha-Thiosialoside-containing dendrimers scaffolded on an orthogonally p rotected 3,3'-iminobis(propylamine) core were efficiently prepared via Cbz-protecting group and HOBt/DIC coupling strategies. The potential of these sialodendrimers to cross-link and precipitate Limax flavus le ctin (LFA) was confirmed by turbidimetric analysis. When tested in enz yme-linked lectin inhibition assays using human al-acid glycoprotein ( orosomucoid) as coating antigen and horseradish peroxidase-labeled LFA for detection di- (31), tetra- (32), octa- (33), and hexadecavalent ( 34) divergent dendrimers Showed IC50 values of 176, 11.8, 206, and 425 nM while the tethered structures with valencies of four (14), six (20 ), eight (25), and twelve (30) exhibited IC50 values of 58.7, 16.9, 17 .5, and 8.22 nM, respectively. These data represent 3.5 (34) to 182 (3 0) fold increases in inhibitory potential over monovalent -deoxy-D-gly cero-alpha-D-galacto-2-nonulopyranosyl azide used as a standard (IC50 1500 nM). The tethered alpha-sialodendrimers appeared to have structur al organizations more suitable than the divergent dendrimers for the s olid phase inhibition of the binding of human al-acid glycoprotein to LFA. All alpha-sialodendrimers are currently being evaluated as inhibi tors of human erythrocyte hemagglutination by Influenza viruses.