Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN.

Abstract

In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.

• Authors: Khouloud Chakroun, Marwa Taouai, Vanessa Porkolab, Joanna Luczkowiak, Roman Sommer, Coraline Cheneau, David Mathiron, Mohamed Amine Ben Maaouia, Serge Pilard, Rym Abidi, Catherine Mullié, Franck Fieschi, Peter J Cragg, Franck Halary, Rafael Delgado, Mohammed Benazza
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 19 Pg. 14332-14343 (10 14 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34524803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Cell Adhesion Molecules
• DC-specific ICAM-3 grabbing nonintegrin
• Glycoconjugates
• Glycoproteins
• Hydroxamic Acids
• Lectins, C-Type
• Phenols
• Receptors, Cell Surface
• Recombinant Proteins
• Viral Proteins
• calix(4)arene
• Calixarenes

Topics

• Antiviral Agents (chemistry, metabolism, pharmacology)
• Calixarenes (chemistry)
• Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
• Cell Line
• Cytomegalovirus (metabolism)
• Dendritic Cells (cytology, metabolism)
• Ebolavirus (physiology)
• Glycoconjugates (chemistry, metabolism, pharmacology)
• Glycoproteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Hydroxamic Acids (chemistry)
• Jurkat Cells
• Lectins, C-Type (antagonists & inhibitors, metabolism)
• Models, Biological
• Phenols (chemistry)
• Protein Binding
• Receptors, Cell Surface (antagonists & inhibitors, metabolism)
• Recombinant Proteins (biosynthesis, chemistry, isolation & purification)
• Viral Proteins (antagonists & inhibitors, genetics, metabolism)