title: Closing two doors of viral entry: intramolecular combination of a coreceptor- and fusion inhibitor of HIV-1.
abstract: We describe a novel strategy in which two inhibitors of HIV viral entry were incorporated into a single molecule. This bifunctional fusion inhibitor consists of an antibody blocking the binding of HIV to its co-receptor CCR5, and a covalently linked peptide which blocks envelope mediated virus-cell fusion. This novel bifunctional molecule is highly active on CCR5- and X4-tropic viruses in a single cycle assay and a reporter cell line with IC50 values of 0.03-0.05 nM. We demonstrated that both inhibitors contribute to the antiviral activity. In the natural host peripheral blood mononuclear cells (PBMC) the inhibition of CXCR4-tropic viruses is dependant on the co-expression of CCR5 and CXCR4 receptors. This bifunctional inhibitor may offer potential for improved pharmacokinetic parameters for a fusion inhibitor in humans and the combination of two active antiviral agents in one molecule may provide better durability in controlling the emergence of resistant viruses.
authors.affiliation: 1Pharmaceuticals Division, Roche Penzberg, Penzberg, Germany. erhard.kopetzki@roche.com
authors.forename: Erhard
authors.initials: E
authors.lastname: Kopetzki
authors.forename: Andreas
authors.initials: A
authors.lastname: Jekle
authors.forename: Changhua
authors.initials: C
authors.lastname: Ji
authors.forename: Eileen
authors.initials: E
authors.lastname: Rao
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Stephan
authors.initials: S
authors.lastname: Fischer
authors.forename: Nick
authors.initials: N
authors.lastname: Cammack
authors.forename: Surya
authors.initials: S
authors.lastname: Sankuratri
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Heilek
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008561:Membrane Fusion / Q000187:drug effects; D051379:Mice; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D053585:Virus Attachment / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins