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 DC-SIGN-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 –, researcher of the IBS in Grenoble and from the IOCB in Prague, 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 they also addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. They 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 a new paradigm to optimize multivalent ligands targeting oligomeric receptors.
Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor. Vanessa Porkolab, Martin Lepšík, Stefania Ordanini, Alexander St John, Aline Le Roy, Michel Thépaut, Emanuele Paci, Christine Ebel, Anna Bernardi, and Franck Fieschi. ACS Central Science 2023, doi.org/10.1021/acscentsci.2c01136
Contact : Franck Fieschi (IBS/Membrane and Pathogens Group)