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

Area of Science:

• Carbohydrate Chemistry
• Virology
• Materials Science

Background:

• Multivalent glycodendrimers are crucial for understanding carbohydrate-protein interactions.
• Scaffold design significantly impacts specificity and affinity in these interactions.
• Previous research established glucuronic acid dendrons with moderate affinity for dengue virus proteins.

Purpose of the Study:

• To synthesize and characterize novel glucuronic acid-based dendrimers with varying scaffold flexibility (rigid, semirigid, flexible).
• To evaluate the binding affinity of these new glycodendrimers to the dengue virus envelope protein.
• To explore structure-activity relationships between scaffold flexibility and binding efficacy.

Main Methods:

• Chemical synthesis of glycodendrimers using copper-catalyzed azide-alkyne cycloaddition.
• Optimization of synthetic strategies for efficient glycodendrimer preparation.
• Surface plasmon resonance (SPR) for quantitative binding analysis.
• Molecular modeling to elucidate binding mechanisms.

Main Results:

• Successful synthesis of rigid, semirigid, and flexible glucuronic acid dendrimers with good yields.
• Flexible glycodendrimers (12b and 12c) exhibited significantly enhanced binding affinity (K_D = 0.487 μM and 0.624 μM, respectively) to the dengue virus envelope protein.
• Binding affinities were 45 and 35 times greater than previously reported rigid dendrons.
• Molecular modeling provided insights into the differential binding behaviors.

Conclusions:

• Flexible scaffolds in glycodendrimers substantially improve binding affinity to dengue virus envelope protein.
• The developed synthetic process is efficient and versatile for creating potential antiviral agents.
• These findings pave the way for designing targeted therapeutics against dengue virus infections.