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 journalArticleResearchpeer-review

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

Fingerprint

C-Type Lectins
Glycoproteins
Viruses
Calixarenes
Ligands
Alkynes
Water
Viral Antigens
Macrophages
Surface plasmon resonance
Pathogens
Cell membranes
Polysaccharides
Dendritic Cells
Proteins

Keywords

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

Cite this

Taouai, Marwa ; Porkolab, Vanessa ; Chakroun, Khouloud ; Cheneau, Coraline ; Luczkowiak, Joanna ; Abidi, Rym ; Lesur, David ; Cragg, Peter ; Halary, Franck ; Delgado, Rafael ; Fieschi, Franck ; Benazza, Mohammed . / Unprecedented Thiacalixarene Fucoclusters as Strong Inhibitors of Ebola cis-Cell Infection and HCMV-gB Glycoprotein/DC-SIGN C-type Lectin Interaction. In: Bioconjugate Chemistry. 2019 ; Vol. 30, No. 4. pp. 1114-1126.
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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.",
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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, vol. 30, no. 4, pp. 1114-1126. https://doi.org/10.1021/acs.bioconjchem.9b00066

Unprecedented Thiacalixarene Fucoclusters as Strong Inhibitors of Ebola cis-Cell Infection and HCMV-gB Glycoprotein/DC-SIGN C-type Lectin Interaction. / Taouai, Marwa ; Porkolab, Vanessa ; Chakroun, Khouloud ; Cheneau, Coraline ; Luczkowiak, Joanna; Abidi, Rym ; Lesur, David ; Cragg, Peter; Halary, Franck ; Delgado, Rafael ; Fieschi, Franck; Benazza, Mohammed .

In: Bioconjugate Chemistry, Vol. 30, No. 4, 26.03.2019, p. 1114-1126.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Porkolab, Vanessa

AU - Chakroun, Khouloud

AU - Cheneau, Coraline

AU - Luczkowiak, Joanna

AU - Abidi, Rym

AU - Lesur, David

AU - Cragg, Peter

AU - Halary, Franck

AU - Delgado, Rafael

AU - Fieschi, Franck

AU - Benazza, Mohammed

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