Efficient solid-phase synthesis of dendritic a-thiosialoside inhibitors of influenza A virus haemagglutinin are described using hyperbranched L-lysine core structures.
Carbohydrate−protein binding interactions can be
greatly amplified using the cluster or multivalent effect.
In previous studies, sialylated multibranched l-lysine
dendrimers were found to be potent inhibitors of the
hemagglutination of human erythrocytes by Influenza viruses.
In order to further the understanding of multivalency
and its role in carbohydrate−protein interactions, glycoconjugates
with differing carbohydrate densities, conformations,
and interglycosidic spacings must be prepared. The synthesis and
biological testing of structurally similar divergent
and tethered α-sialodendrimers are presented herein.
α-Thiosialoside-containing dendrimers scaffolded on
an
orthogonally protected 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
lectin
(LFA) was confirmed by turbidimetric analysis. When tested in
enzyme-linked lectin inhibition assays using human
α1-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 (30) fold increases
in
inhibitory potential over monovalent
5-acetamido-5-deoxy-d-glycero-α-d-galacto-2-nonulopyranosyl
azide used as
a standard (IC50 1500 nM). The tethered
α-sialodendrimers appeared to have structural organizations more
suitable
than the divergent dendrimers for the solid phase inhibition of the
binding of human α1-acid glycoprotein to
LFA.
All α-sialodendrimers are currently being evaluated as
inhibitors of human erythrocyte hemagglutination by
Influenza
viruses.
Proof that multivalency amplifies individual carbohydrate-protein interactions is growing. N-Acetylglucosamine (GlcNAc)-based dendrimers with valencies of two (9), four (10), and eight (11) were prepared in fair to excellent yields (65-99%) on the basis of the rational scaffolding of L-lysine on solid phase using established Fmoc and HOBt chemistry. These GlcNAc dendrimers were then further transformed enzymatically (79-90% yields) into dendritic N-acetyllactosamine (LacNAc) derivatives [di-(12), tetra-(13), and octavalent (14)] using UDPglucose, UDP-glucose 4'-epimerase, and GlcNAc beta-1,4-galactosyltransferase. GlcNAc and LacNAc dendrimers were used to inhibit lectin-porcine stomach mucin interactions. Wheat germ agglutinin and Erythrina cristagalli lectin were used for GlcNAc and LacNAc dendrimers, respectively. Di-, tetra-, and octavalent GlcNAc dendrimers exhibited IC50S of 3100, 509, and 88 microM (6200, 2040, and 703 microM, with respect to monomeric GlcNAc content). IC50s for the LacNAc series were 341, 143, and 86 microM (682, 574, and 692 microM, as compared with monomeric LacNAc content). These data represent more than 20-fold increases in inhibitory potential for dendritic GlcNAc as compared to that for monomeric GlcNAc. Studies with E. cristagalli do not reveal significant increased inhibitory potential with multivalency.
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