Powerful avidity with a limited valency for virus-attachment blockers on DC SIGN: Combining chelation and statistical rebinding with structural plasticity of the receptor

09 August 2022, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

The C-type lectin receptor DC-SIGN has been highlighted as co-receptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DCSIGN- dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects - chelation, clustering and statistical rebinding – we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed Surface Plasmon Resonance oriented-surface methodology. Using molecular modelling we addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nM affinity despite a limited valency. This multi-faceted experimental-theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses.

Keywords

C-type lectin receptors
multivalency
avidity
surface plasmon resonance
glycomimetics
chelation binding mode
molecular modelling
Emerging virus
SARS-CoV-2
Dengue

Supplementary materials

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supp info file
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compound synthesis, spr data, protocols for biophysical characterization, molecular modeling, consideration on clustering binding mode
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movie1
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DC-SIGN side
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movie2
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DC-SIGN top
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