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Probing scaffold size effects on multivalent lectin-glycan binding affinity, thermodynamics and antiviral properties
Rahman Basaran1, Darshita Budhadev1, Amy Kempf2
1School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. d.zhou@leeds.ac.uk.
Nanoscale
|July 10, 2024
Summary
Larger gold nanoparticles (GNPs) functionalized with specific sugars (DiMan) significantly enhance multivalent lectin-glycan interactions (MLGIs). This breakthrough improves understanding of viral infections and leads to more potent antiviral glycoconjugate therapeutics.
Area of Science:
- Biophysics
- Nanotechnology
- Virology
Background:
- Multivalent lectin-glycan interactions (MLGIs) are crucial for viral infections and immune responses.
- Understanding MLGI mechanisms and biophysical properties is vital for developing targeted glycoconjugate therapeutics.
- Previous nanoparticle probes had limitations in maximizing MLGI affinity and specificity.
Purpose of the Study:
- To systematically investigate the impact of gold nanoparticle (GNP) scaffold size and glycan density on MLGI affinities, thermodynamics, and antiviral properties.
- To develop and validate a new assay for quantifying MLGI affinities with reduced interference.
- To evaluate the antiviral potency of GNP-glycan probes against DC-SIGN and DC-SIGNR mediated viral entry.
Main Methods:
- Synthesis of α-manno-α-1,2-biose (DiMan) functionalized GNPs with varying sizes (5, 13, 27 nm) and glycan densities.
- Development of a GNP fluorescence quenching assay to quantify MLGI affinities.
- Determination of MLGI thermodynamics using temperature-dependent affinity and Van't Hoff analyses.
- Assessment of antiviral potency against DC-SIGN/R mediated pseudo-Ebola virus entry.
Main Results:
- Increasing GNP scaffold size significantly enhances MLGI affinity.
- GNP-DiMan binding to DC-SIGN/R is enthalpy-driven, with enhanced binding free energy as size increases.
- Larger GNP probes exhibit significantly enhanced antiviral potency, with 27 nm DiMan-GNPs showing potent inhibition of pseudo-Ebola virus entry (EC50 ~23-49 pM).
Conclusions:
- Gold nanoparticles functionalized with specific glycans serve as effective tools for quantifying MLGI biophysical parameters.
- Increasing GNP scaffold size is a key strategy for enhancing MLGI affinities and antiviral potencies.
- The developed 27 nm DiMan-GNP probe represents a highly potent glycoconjugate inhibitor for DC-SIGN/R-mediated viral infections.
