title: A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus.
abstract: DC-SIGN is a C-type lectin receptor on antigen presenting cells (dendritic cells) which has an important role in some viral infection, notably by HIV and Dengue virus (DV). Multivalent presentation of carbohydrates on dendrimeric scaffolds has been shown to inhibit DC-SIGN binding to HIV envelope glycoprotein gp120, thus blocking viral entry. This approach has interesting potential applications for infection prophylaxis. In an effort to develop high affinity inhibitors of DC-SIGN mediated viral entry, we have synthesized a group of glycodendrimers of different valency that bear different carbohydrates or glycomimetic DC-SIGN ligands and have studied their DC-SIGN binding activity and antiviral properties both in an HIV and a Dengue infection model. Surface Plasmon Resonance (SPR) competition studies have demonstrated that the materials obtained bind efficiently to DC-SIGN with IC50s in the μm range, which depend on the nature of the ligand and on the valency of the scaffold. In particular, a hexavalent presentation of the DC-SIGN selective antagonist 4 displayed high potency, as well as improved accessibility and chemical stability relative to previously reported dendrimers. At low μm concentration the material was shown to block both DC-SIGN mediated uptake of DV by Raji cells and HIV trans-infection of T cells.
authors: Universita' degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy.
authors: Norbert
authors: N
authors: Varga
authors: Univ. Grenoble Alpes, Institut de Biologie Structurale (IBS), F-38027 Grenoble, France; CEA, DSV, IBS, F-38027 Grenoble, France; CNRS, IBS, F-38027 Grenoble, France.
authors: Ieva
authors: I
authors: Sutkeviciute
authors: Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Americo Vespucio 49, 41092 Sevilla, Spain.
authors: Renato
authors: R
authors: Ribeiro-Viana
authors: Università degli Studi di Milano, Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Via GB Grassi 74, 20157 Milano, Italy.
authors: Angela
authors: A
authors: Berzi
authors: INSERM U944, Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors: Rasika
authors: R
authors: Ramdasi
authors: Universita' degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy.
authors: Anna
authors: A
authors: Daghetti
authors: Universita' degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy.
authors: Gerolamo
authors: G
authors: Vettoretti
authors: INSERM U944, Laboratoire de Pathologie et Virologie Moléculaire, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
authors: Ali
authors: A
authors: Amara
authors: Università degli Studi di Milano, Dipartimento di Fisiopatologia Medico-chirurgica e dei Trapianti, Via F.lli Cervi 93, 20090 Segrate, Italy; Fondazione Don Gnocchi IRCCS, Via Capecelatro 66, 20148 Milano, Italy.
authors: Mario
authors: M
authors: Clerici
authors: Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Americo Vespucio 49, 41092 Sevilla, Spain.
authors: Javier
authors: J
authors: Rojo
authors: Univ. Grenoble Alpes, Institut de Biologie Structurale (IBS), F-38027 Grenoble, France; CEA, DSV, IBS, F-38027 Grenoble, France; CNRS, IBS, F-38027 Grenoble, France.
authors: Franck
authors: F
authors: Fieschi
authors: Universita' degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy; CNR-ISTM, Institute of Molecular Science and Technologies, Milan, Italy. Electronic address: anna.bernardi@unimi.it.
authors: Anna
authors: A
authors: Bernardi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D015815:Cell Adhesion Molecules; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology; D003716:Dengue Virus / Q000187:drug effects* / Q000472:pathogenicity*; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D020349:Surface Plasmon Resonance; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000998:Antiviral Agents; D015815:Cell Adhesion Molecules; D050091:Dendrimers; D006027:Glycosides; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C000621955:glycodendrimer 13.3
keywords: DC-SIGN; Dengue; Glycodendrimers; Glycomimetics; HIV; Nanotechnology