The C-type lectin receptors DC-SIGN and L-SIGN have been highlighted as co receptors for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been described as able to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such system remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects of Polyman26 - chelating, clustering and statistical rebinding – we studied a series of dendrimer constructs with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric dendritic cell lectin receptor DC-SIGN. Different binding properties of these compounds have been studied with a range of biophysical techniques. 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 provide detailed understanding of multivalent ligand/multimericprotein 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.

Powerful avidity with a limited valency for virus-attachment blockers on DC-SIGN: Combining chelation and statistical rebinding with structural plasticity of the receptor / V. Porkolab, M. Lepšík, S. Ordanini, A. St John, A. Le Roy, M. Thépaut, E. Paci, C. Ebel, A. Bernardi, F. Fieschi. - (2022 Mar 30). [10.26434/chemrxiv-2022-4n79q]

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

Ordanini, Stefania;Bernardi, Anna;
2022-03-30

Abstract

The C-type lectin receptors DC-SIGN and L-SIGN have been highlighted as co receptors for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been described as able to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such system remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects of Polyman26 - chelating, clustering and statistical rebinding – we studied a series of dendrimer constructs with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric dendritic cell lectin receptor DC-SIGN. Different binding properties of these compounds have been studied with a range of biophysical techniques. 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 provide detailed understanding of multivalent ligand/multimericprotein 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.
C-type lectin receptors; multivalency; avidity; surface plasmon resonance; glycomimetics; chelation binding mode; molecular modelling; Emerging virus; SARS-CoV-2; Dengue
Settore CHIM/06 - Chimica Organica
https://chemrxiv.org/engage/chemrxiv/article-details/6243789c437a061ac4ec25a8
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/925565
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