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

• Published in: Journal of medicinal chemistry 2021-10, Vol.64 (19), p.14332-14343
• Main Authors: Chakroun, Khouloud, Taouai, Marwa, Porkolab, Vanessa, Luczkowiak, Joanna, Sommer, Roman, Cheneau, Coraline, Mathiron, David, Ben Maaouia, Mohamed Amine, Pilard, Serge, Abidi, Rym, Mullié, Catherine, Fieschi, Franck, Cragg, Peter J, Halary, Franck, Delgado, Rafael, Benazza, Mohammed
• Format: Article
• Language: English
• Subjects: Chemical Sciences
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00818

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.