Unprecedented Thiacalixarene Fucoclusters as Strong Inhibitors of Ebola cis-Cell Infection and HCMV-gB Glycoprotein/DC-SIGN C-type Lectin Interaction

Marwa Taouai, Vanessa Porkolab, Khouloud Chakroun, Coraline Cheneau, Joanna Luczkowiak, Rym Abidi, David Lesur, Peter Cragg, Franck Halary, Rafael Delgado, Franck Fieschi, Mohammed Benazza

Research output: Contribution to journalArticle

Abstract

Glycan-protein interactions control numerous biological events from cell-cell recognition and signaling to pathogen host cell attachment for infections. To infect cells, some viruses bind to immune cells with the help of DC-SIGN (dendritic cell [DC]-specific ICAM3-grabbing nonintegrin) C-type lectin expressed on dendritic and macrophage cell membranes, via their envelope protein. Prevention of this infectious interaction is a serious therapeutic option. Here, we describe the synthesis of the first water-soluble tetravalent fucocluster pseudopeptide-based 1,3-alternate thiacalixarenes as viral antigen mimics designed for the inhibition of DC-SIGN, to prevent viral particle uptake. Their preparation exploits straightforward convergent strategies involving one-pot Ugi four-component (Ugi-4CR) and azido-alkyne click chemistry reactions as key steps. Surface plasmon resonance showed strong inhibition of DC-SIGN interaction properties by tetravalent ligands designed with high relative potencies and β avidity factors. All ligands block DC-SIGN active sites at nanomolar IC 50 preventing cis-cell infection by Ebola viral particles pseudotyped with EBOV glycoprotein (Zaire species of Ebola virus) on Jurkat cells that express DC-SIGN. In addition, we observed strong inhibition of DC-SIGN/human cytomegalovirus (HCMV)-gB recombinant glycoprotein interaction. This finding opens the way to the simple development of new models of water-soluble glycocluster-based thia-calixarenes with wide-ranging antimicrobial activities.

Original languageEnglish
Pages (from-to)1114-1126
Number of pages13
JournalBioconjugate Chemistry
Volume30
Issue number4
DOIs
Publication statusPublished - 26 Mar 2019

Keywords

  • Ebola virus
  • EBOV
  • HCMV
  • DC-SIGN
  • Calixarene
  • Thiacalixarene
  • Ugi-4CR

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    Taouai, M., Porkolab, V., Chakroun, K., Cheneau, C., Luczkowiak, J., Abidi, R., Lesur, D., Cragg, P., Halary, F., Delgado, R., Fieschi, F., & Benazza, M. (2019). Unprecedented Thiacalixarene Fucoclusters as Strong Inhibitors of Ebola cis-Cell Infection and HCMV-gB Glycoprotein/DC-SIGN C-type Lectin Interaction. Bioconjugate Chemistry, 30(4), 1114-1126. https://doi.org/10.1021/acs.bioconjchem.9b00066