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.
Bibliographical noteFunding Information:
Support from the “Conseil Régional de Picardie” and the LG2A-UMR7378-CNRS research group is gratefully acknowledged. K.C. and M.T. were financially supported by the Tunisian government. This work used the platforms of the Grenoble Instruction Centre (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL), notably SPR and MP3 platforms, with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX- 49-01) within the Grenoble Partnership for Structural Biology (PSB). V.P. was supported by la Région Rhône-Alpes. Research in RD lab is supported by grants from the Instituto de Investigación Carlos III (FIS PI 1801007) by the European Union Commission Horizon 2020 Framework Programme: Project VIRUSCAN FETPROACT-2016: 731868 and by Fundación Caixa-Health Research (Project StopEbola). The authors are grateful to the Chemical Biology of Carbohydrates, Helmholtz, Institute for Pharmaceutical Research Saarland, 66123 Saarbrücken, Germany, for the LecB inhibition assays. The authors thank the “Développement et Transfert à la Clinique platform ( http://www.cicnantes.fr/fr/component/glossary/Glossaire-1/C/CIC-35/ , CIC Biothérapies CBT 0503, CHU Nantes, France)” for providing elutriated monocytes, clinical-grade cytokines, and human serum albumin. The ARMINA Consortium (no. 201209680) supported Coraline Chéneau’s salary.
- Drug Discovery
- Molecular Medicine