title: Monovalent mannose-based DC-SIGN antagonists: targeting the hydrophobic groove of the receptor.
abstract: Dendritic cell-specific, intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a C-type lectin expressed specifically on dendritic cells. It is a primary site for recognition and binding of various pathogens and thus a promising therapeutic target for inhibition of pathogen entry and subsequent prevention of immune defense cell infection. We report the design and synthesis of d-mannose-based DC-SIGN antagonists bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties incorporated to target the hydrophobic groove of the receptor. The designed glycomimetics were evaluated by in vitro assay of the isolated DC-SIGN extracellular domain for their ability to compete with HIV-1 gp120 for binding to the DC-SIGN carbohydrate recognition domain. Compounds 14d and 14e, that display IC50 values of 40 μM and 50 μM, are among the most potent monovalent DC-SIGN antagonists reported. The antagonistic effect of all the synthesized compounds was further evaluated by a one-point in vitro assay that measures DC adhesion. Compounds 14d, 14e, 18d and 18e were shown to act as functional antagonists of DC-SIGN-mediated DC adhesion. The binding mode of 14d was also studied by molecular docking and molecular dynamics simulation, which revealed flexibility of 14d in the binding site and provides a basis for further optimization.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašić
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: David
authors.initials: D
authors.lastname: Hajšek
authors.affiliation: Blood Transfusion Center of Slovenia, Šlajmerjeva 6, 1000 Ljubljana, Slovenia.
authors.forename: Urban
authors.initials: U
authors.lastname: Švajger
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Jernej
authors.initials: J
authors.lastname: Luzar
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia; Jožef Stefan Institute, Department of Biotechnology, Jamova 39, 1000 Ljubljana, Slovenia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Obermajer
authors.affiliation: Univ. Grenoble Alpes, Institut de Biologie Structurale (IBS), F-38000 Grenoble, France; CNRS, IBS, F-38000 Grenoble, France; CEA, IBS, F-38027 Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petit-Haertlein
authors.affiliation: Univ. Grenoble Alpes, Institut de Biologie Structurale (IBS), F-38000 Grenoble, France; CNRS, IBS, F-38000 Grenoble, France; CEA, IBS, F-38027 Grenoble, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Fieschi
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: marko.anderluh@ffa.uni-lj.si.
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
mesh_terms: D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008358:Mannose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D008358:Mannose; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
keywords: Anti-infectives; Carbohydrates; DC-SIGN; DC-SIGN antagonists; Glycomimetics; Lectins