Vol. 57, Issue 1, 116-124, January 2000

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 Daelemans, Dominique Schols, Myriam Witvrouw, Christophe Pannecouque, Sigrid Hatse, Sonia van Dooren, François Hamy, Thomas Klimkait,¹ Erik de Clercq, and Anne-Mieke VanDamme

Rega 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 Novartis Pharmaceuticals, Pharma Research, Basel, Switzerland (F.H., T.K.)

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-1_LAV 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.