Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

0569104 - ÚOCHB 2024 RIV US eng J - Článek v odborném periodiku
Porkolab, V. - Lepšík, Martin - Ordanini, S. - St John, A. - Le Roy, A. - Thépaut, M. - Paci, E. - Ebel, C. - Bernardi, A. - Fieschi, F.
Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor.
ACS Central Science. Roč. 9, č. 4 (2023), s. 709-718. ISSN 2374-7943. E-ISSN 2374-7951
Grant CEP: GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: lectin receptors * trans-infection * ligands
Obor OECD: Physical chemistry
Impakt faktor: 18.2, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1021/acscentsci.2c01136

The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor 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 ─ 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 modeling 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 nanomolar affinity despite a limited valency. This multifaceted 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.
Trvalý link: https://hdl.handle.net/11104/0340429