Vol. 63, Issue 1, 203-210, January 2003

The Anti-HIV Potency of Cyclotriazadisulfonamide Analogs Is Directly Correlated with Their Ability to Down-Modulate the CD4 Receptor

Kurt Vermeire, Thomas W. Bell, Heung-Jin Choi, Qi Jin, Meinrado F. Samala, Andrej Sodoma, Erik De Clercq, and Dominique Schols

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium (K.V., E.D.C., D.S.); Department of Chemistry, University of Nevada, Reno, Nevada (T.W.B., Q.J., M.F.S.); Department of Industrial Chemistry, Kyungpook National University, Daegu, Korea (H.-J.C.); and Department of Chemistry, State University of New York, Stony Brook, New York (A.S.)

9-Benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane (CADA) has been identified as a novel antiviral lead compound with significant anti-human immunodeficiency virus and anti-human herpesvirus 7 activity. Surprisingly, this compound selectively decreased the expression of the CD4 glycoprotein, the primary receptor needed for the entry of both viruses. Herein, we describe the CD4 down-modulating and antiviral potencies of more than 25 CADA derivatives. Flow cytometric evaluation of cellular CD4 receptor expression in T cells demonstrated the specific CD4 down-modulating capacity of the CADA derivatives, with IC₅₀ values similar to those obtained in the antiviral assays. The close correlation observed between the CD4 down-regulating and anti-HIV potencies of the CADA derivatives further points to CD4 receptor down-modulation as the primary mode of antiviral action for this group of compounds.