Human Immunodeficiency Virus Type 1 Entry Inhibitors Selected on Living Cells from a Library of Phage Chemokines
| Autor: | Robin E. Offord, Oliver Hartley, Anouk Heimann, Karim Dorgham, Danielle Perez-Bercoff, Fabrice Cerini, Guy Gorochov, Hubert François Gaertner, Gianfranco Pancino, Patrice Debré |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
CCR1
Chemokine Receptors CCR5 Anti-HIV Agents Chemokine receptor CCR5 Immunology CCR3 CHO Cells C-C chemokine receptor type 6 ddc:616.07 Membrane Fusion/drug effects Chemokine CCL5/analogs & derivatives/genetics/pharmacology Binding Competitive Membrane Fusion Microbiology CXCR4 CCL5 Cell Line Chemokine receptor Competitive Peptide Library Cricetinae Virology Anti-HIV Agents/pharmacology Receptors Vaccines and Antiviral Agents Animals Humans ddc:576 Chemokines/genetics/pharmacology Chemokine CCL5 biology Binding Molecular biology CCR5/metabolism Insect Science Mutation HIV-1 biology.protein Chemokines HIV-1/drug effects/pathogenicity |
| Zdroj: | Journal of Virology, Vol. 77, No 12 (2003) pp. 6637-44 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.77.12.6637-6644.2003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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