Biological and Medicinal Chemistry

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

Authors

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.

Version notes

Improvement in the main text and in some analysis. Improvement in the molecular dynamic part (mainly in the description in the SI). Some new references added, and link to the molecular dynamic parameters deposited in mendeley data

Content

Thumbnail image of Porkolabetal et al-chemRixv-V3.pdf

Supplementary material

Thumbnail image of Supporting information-chemRXiv-V3.pdf
supp info file
compound synthesis, spr data, protocols for biophysical characterization, molecular modeling, consideration on clustering binding mode
Thumbnail image of Movie-2us-DC-SIGN-side.mpg
movie1
DC-SIGN side
Thumbnail image of Movie-2us-DC-SIGN-top.mpg
movie2
DC-SIGN top