Human immunodeficiency virus type 1 entry inhibitors selected on living cells from a library of phage chemokines

Article Article scientifique Article Human immunodeficiency virus type 1 entry inhibitors selected on living cells from a library of phage chemokines eng 2003 author Hartley Oliver 0000-0002-2283-8379 507767 author Dorgham Karim author Perez-Bercoff Danielle author Cerini Fabrice 23116 author Heimann Anouk 500149 author Gaertner Hubert François 84280 author Offord Robin Ewart 25437 author Pancino Gianfranco author Debré Patrice author Gorochov Guy 6637-6644 10.1128/JVI.77.12.6637–6644.2003 12767983 0022-538X The chemokine receptors CCR5 and CXCR4 are promising non-virus-encoded targets for human immunodeficiency virus (HIV) therapy. We describe a selection procedure to isolate mutant forms of RANTES (CCL5) with antiviral activity considerably in excess of that of the native chemokine. The phage-displayed library of randomly mutated and N-terminally extended variants was screened by using live CCR5-expressing cells, and two of the selected mutants, P1 and P2, were further characterized. Both were significantly more potent HIV inhibitors than RANTES, with P2 being the most active (50% inhibitory concentration of 600 pM in a viral coat-mediated cell fusion assay, complete protection of target cells against primary HIV type 1 strains at a concentration of 10 nM). P2 resembles AOP-RANTES in that it is a superagonist of CCR5 and potently induces receptor sequestration. P1, while less potent than P2, has the advantage of significantly reduced signaling activity via CCR5 (30% of that of RANTES). Additionally, both P1 and P2 exhibit not only significantly increased affinity for CCR5 but also enhanced receptor selectivity, retaining only trace levels of signaling activity via CCR1 and CCR3. The phage chemokine approach that was successfully applied here could be adapted to other chemokine-chemokine receptor systems and used to further improve the first-generation mutants reported in this paper. Animals Anti-HIV Agents/pharmacology Binding Competitive CHO Cells Cell Line Chemokine CCL5/analogs & derivatives/genetics/pharmacology Chemokines/genetics/pharmacology Cricetinae HIV-1/drug effects/pathogenicity Humans Membrane Fusion/drug effects Mutation Peptide Library Receptors CCR5/metabolism Dewey 576 Dewey 616.07 136 Département de biologie structurale et bioinformatique 21E 137 Département de pathologie et immunologie 21F false 497 HIV 835 Journal of virology 77 12 41c99333-aba3-4e92-9db4-ab897d2a4acf Article Public file1.pdf 513402 application/pdf openAccess Faculté de médecine / Section de médecine fondamentale / Département de biologie structurale et bioinformatique Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Human immunodeficiency virus type 1 entry inhibitors selected on living cells from a library of phage chemokines	Journal of virology			2003	492	332

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Heimann, Anouk