The Anti-HIV potency of cyclotriazadisulfonamide analogs is directly correlated with their ability to down-modulate the CD4 receptor.
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 IC(50) 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.
Vermeire
Kurt
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
Bell
Thomas W
TW
Choi
Heung-Jin
HJ
Jin
Qi
Q
Samala
Meinrado F
MF
Sodoma
Andrej
A
De Clercq
Erik
E
Schols
Dominique
D
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D015497:HIV-1 / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013223:Statistics as Topic; D013449:Sulfonamides / Q000494:pharmacology*
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D006573:Heterocyclic Compounds, 1-Ring; D013449:Sulfonamides