A Second Target for the Peptoid Tat/Transactivation Response Element Inhibitor CGP64222: Inhibition of Human Immunodeficiency Virus Replication by Blocking CXC-Chemokine Receptor 4-Mediated Virus Entry
- Dirk Daelemans1,
- Dominique Schols1,
- Myriam Witvrouw1,
- Christophe Pannecouque1,
- Sigrid Hatse1,
- Sonia van Dooren1,
- François Hamy2,
- Thomas Klimkait1,2,
- Erik de Clercq1 and
- Anne-Mieke VanDamme1
- 1Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium (D.D., D.S., M.W., C.P., S.H., S. Van D., E. De C., A.-M.V.); and 2Novartis Pharmaceuticals, Pharma Research, Basel, Switzerland (F.H., T.K.)
Abstract
The peptoid CGP64222 has been previously demonstrated to inhibit the human immunodeficiency virus (HIV) Tat/transactivation response element complex formation. It has previously been shown that CGP64222 selectively inhibits HIV-1 long terminal repeat-driven gene expression and HIV-1LAV replication in lymphocytes. Here, we show that CGP64222 inhibits the replication of a wide range of laboratory strains of HIV-1 and HIV-2 in MT-4 cells. However, CGP64222 proved inactive in MT-4 cells against HIV-1 strains that are resistant to the bicyclams. The bicyclams are known to specifically interact with CXC-chemokine receptor 4, the main coreceptor used by T-tropic HIV strains to enter the cells. Mechanism of action studies revealed that CGP64222 can inhibit the HIV replicative cycle, also through a selective interaction with the CXC-chemokine receptor 4 coreceptor.
Footnotes
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Send reprint requests to: Dr. Dirk Daelemans, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: Dirk.Daelemans{at}uz.kuleuven.ac.be
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↵1 Current address: Institute for Medical Mikrobiology, University of Basle, Petersplatz 10 CH-4003 Basle, Switzerland.
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This work was supported by grants from the Belgian Nationaal Fonds voor Wetenschappelijk Onderzoek (G.3304.96), the Geconcerteerde Onderzoeksacties (GOA 95/5), and the Biomedical Research Programme of the European Union (EU Biomed. 2 grant BMH4-CT-95-1634). D.D. acknowledges a fellowship from the Flemish Institute supporting Scientific-Technological Research in Industry (IWT).
- Abbreviations:
- HIV
- human immunodeficiency virus
- CMV
- cytomegalovirus
- LTR
- long terminal repeat
- FITC
- fluorescein isothiocyanate
- mAb
- monoclonal antibody
- MFI
- mean fluorescence intensity
- M-tropic
- macrophage-tropic
- PBL
- peripheral blood lymphocyte
- PCR
- polymerase chain reaction
- PMA
- phorbol-12-myristate-13-acetate
- RANTES
- regulated on activation normal T cell expressed and secreted
- AZT
- 3′-azido-2′,3′-dideoxythymidine
- Ag
- antigen
- ELISA
- enzyme-linked immunosorbent assay
- RT
- reverse transcription
- SDF-1α
- stromal cell-derived factor-1α
- TAR
- transactivation responsive element
- T-tropic
- T cell line-tropic
- CXCR4
- CXC-chemokine receptor 4
- MIP-1α
- macrophage inflammatory protein 1α
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- Received April 27, 1999.
- Accepted August 20, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
