title: A synthetic heparan sulfate-mimetic peptide conjugated to a mini CD4 displays very high anti- HIV-1 activity independently of coreceptor usage.
abstract: The HIV-1 envelope gp120, which features both the virus receptor (CD4) and coreceptor (CCR5/CXCR4) binding sites, offers multiple sites for therapeutic intervention. However, the latter becomes exposed, thus vulnerable to inhibition, only transiently when the virus has already bound cellular CD4. To pierce this defense mechanism, we engineered a series of heparan sulfate mimicking tridecapeptides and showed that one of them target the gp120 coreceptor binding site with μM affinity. Covalently linked to a CD4-mimetic that binds to gp120 and renders the coreceptor binding domain available to be targeted, the conjugated tridecapeptide now displays nanomolar affinity for its target. Using solubilized coreceptors captured on top of sensorchip we show that it inhibits gp120 binding to both CCR5 and CXCR4 and in peripheral blood mononuclear cells broadly inhibits HIV-1 replication with an IC(50) of 1 nM.
authors.affiliation: CEA, CNRS, Université Joseph Fourier - Grenoble 1, Institut de Biologie Structurale Jean-Pierre Ebel, UMR 5075, 38000 Grenoble, France.
authors.forename: Bridgette Janine
authors.initials: BJ
authors.lastname: Connell
authors.forename: Françoise
authors.initials: F
authors.lastname: Baleux
authors.forename: Yves-Marie
authors.initials: YM
authors.lastname: Coic
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.forename: David
authors.initials: D
authors.lastname: Bonnaffé
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000737:chemistry / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D006497:Heparan Sulfate; D010455:Peptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4