title: Dynamic micelles of mannoside glycolipids are more efficient than polymers for inhibiting HIV-1 trans-infection.
abstract: Mannoside glycolipid conjugates are able to inhibit human immunodeficiency virus type 1 (HIV-1) trans-infection mediated by human dendritic cells (DCs). The conjugates are formed by three building blocks: a linear or branched mannose head, a hydrophilic linker, and a 24-carbon lipid chain. We have shown that, even as single molecules, these compounds efficiently target mannose-binding lectins, such as DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) important for HIV-1 transmission. With the goal to optimize their inhibitory activity by supramolecular structure formation, we have compared saturated and unsaturated conjugates, as single molecules, self-assemblies of dynamic micelles, and photopolymerized cross-linked polymers. Surface plasmon resonance showed that, unexpectedly, polymers of trivalent conjugates did not display a higher binding affinity for DC-SIGN than single molecules. Interactions on a chip or in solution were independent of calcium; however, binding to DCs was inhibited by a calcium chelator. Moreover, HIV-1 trans-infection was mostly inhibited by dynamic micelles and not by rigid polymers. The inhibition data revealed a clear correlation between the structure and molecular assembly of a conjugate and its biological antiviral activity. We present an interaction model between DC-SIGN and conjugates-either single molecules, micelles, or polymers-that highlights that the most effective interactions by dynamic micelles involve both mannose heads and lipid chains. Our data reveal that trivalent glycolipid conjugates display the highest microbicide potential for HIV prophylaxis, as dynamic micelles conjugates and not as rigid polymers.
authors.affiliation: Laboratory of Immunopathology and Therapeutic Chemistry, CNRS UPR 3572/Laboratory of Excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire , 15 rue René Descartes, 67000 Strasbourg, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Schaeffer
authors.forename: Laure
authors.initials: L
authors.lastname: Dehuyser
authors.forename: David
authors.initials: D
authors.lastname: Sigwalt
authors.forename: Vincent
authors.initials: V
authors.lastname: Flacher
authors.forename: Serena
authors.initials: S
authors.lastname: Bernacchi
authors.forename: Olivier
authors.initials: O
authors.lastname: Chaloin
authors.forename: Jean-Serge
authors.initials: JS
authors.lastname: Remy
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mueller
authors.forename: Rachid
authors.initials: R
authors.lastname: Baati
authors.forename: Alain
authors.initials: A
authors.lastname: Wagner
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D004305:Dose-Response Relationship, Drug; D006017:Glycolipids / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000635:transmission*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology*; D008823:Micelles; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D006017:Glycolipids; D008362:Mannosides; D008823:Micelles; D011108:Polymers