1. 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
- Author
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Catherine Mullié, Peter J. Cragg, Franck Fieschi, Vanessa Porkolab, Roman Sommer, Coraline Cheneau, Mohamed Amine Ben Maaouia, Franck Halary, David Mathiron, Rafael Delgado, Mohammed Benazza, Rym Abidi, Serge Pilard, Joanna Luczkowiak, Marwa Taouai, Khouloud Chakroun, Laboratoire de Glycochimie, des Antimicrobiens et des Agro-ressources - UMR CNRS 7378 (LG2A ), Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Instituto de Investigación Hospital Universitario 12 de Octubre, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Plateforme Analytique (PFA), Université de Picardie Jules Verne (UPJV), Laboratoire d'Application de la Chimie aux Ressources et Substances Naturelles de l'Environnement, Faculté des Sciences de Bizerte [Université de Carthage], Université de Carthage - University of Carthage-Université de Carthage - University of Carthage, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, School of Pharmacy & Biomolecular Sciences, University of Brighton, Brighton BN2 4GJ, U.K, Institut de transplantation urologie-néphrologie (ITUN), and Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)
- Subjects
viruses ,Cytomegalovirus ,Receptors, Cell Surface ,Plasma protein binding ,medicine.disease_cause ,Hydroxamic Acids ,Jurkat cells ,Antiviral Agents ,Models, Biological ,Cell Line ,chemistry.chemical_compound ,Jurkat Cells ,Viral Proteins ,Phenols ,Drug Discovery ,medicine ,Humans ,[CHIM]Chemical Sciences ,Avidity ,Lectins, C-Type ,ComputingMilieux_MISCELLANEOUS ,Glycoproteins ,chemistry.chemical_classification ,Ebola virus ,biology ,Cell adhesion molecule ,virus diseases ,Heparan sulfate ,Dendritic Cells ,Ebolavirus ,Virology ,Recombinant Proteins ,DC-SIGN ,chemistry ,biology.protein ,Molecular Medicine ,Calixarenes ,Glycoprotein ,Cell Adhesion Molecules ,Glycoconjugates ,Protein Binding - 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.
- Published
- 2021
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