Exploring Rigid and Flexible Scaffolds to Develop Potent Glucuronic Acid Glycodendrimers for Dengue Virus Inhibition.

Multivalent glycodendrimers are valuable tools for studying carbohydrate-protein interactions, and their scaffolds represent important components to increase specificity and affinity. Previous work by our group described the preparation of a tetravalent glucuronic acid rigid dendron that binds with good affinity to the dengue virus envelope protein ( K D = 22 μM). Herein, the chemical synthesis and binding analysis of three new sets of rigid, semirigid, and flexible glucuronic acid-based dendrimers bearing different levels of multivalency and their interactions with the dengue virus envelope protein are described. The different oligoalkynyl scaffolds were coupled to glucuronic acid azides by a copper-catalyzed azide-alkyne cycloaddition reaction through optimized synthetic strategies to afford the desired glycodendrimers with good yields. Surface plasmon resonance studies have demonstrated that glycodendrimers 12b and 12c , with flexible scaffolds, give the best binding interactions with the dengue virus envelope protein ( 12b : K D = 0.487 μM and 12c : K D = 0.624 μM). Their binding constant values were 45 and 35 times higher than the one obtained in previous studies with a rigid tetravalent glucuronic acid dendron ( K D = 22 μM), respectively. Molecular modeling studies were carried out in order to understand the difference in behavior observed for 12b and 12c . This work reports an efficient glycodendrimer chemical synthesis process that provides an appropriate scaffold that offers an easy and versatile strategy to find new active compounds against the dengue virus.