CADA inhibits human immunodeficiency virus and human herpesvirus 7 replication by down-modulation of the cellular CD4 receptor.
The novel antiviral agent cyclotriazadisulfonamide (CADA) inhibited human immunodeficiency virus (HIV) (IC50, 0.3-3.2 microM) and human herpesvirus 7 (HHV-7) infection (IC50, 0.3-1.5 microM) in T-cell lines and PBMCs. When T-cells were pretreated with CADA for 24 h, they became markedly protected from viral infection. Flow cytometric analysis revealed a significant decrease in the expression of the CD4 glycoprotein, the primary receptor needed for entry of both viruses. Moreover, the antiviral activity of CADA correlated with its ability to down-modulate the CD4 receptor. CADA did not alter the expression of any other cellular receptor (or HIV coreceptor) examined. Time course experiments showed that CD4 down-modulation by CADA differs in mechanism from the effects of aurintricarboxylic acid, which binds directly to CD4, and phorbol myristate acetate, which activates protein kinase C. Further analysis of CD4 mRNA levels suggested that CADA was not involved in the regulation of CD4 expression at a transcriptional level, but very likely at (post) translational levels. This unique mechanism of action makes CADA an important lead in developing new drugs for treatment of AIDS, autoimmune diseases, and inflammatory disorders.
Vermeire
Kurt
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Zhang
Ying
Y
Princen
Katrien
K
Hatse
Sigrid
S
Samala
Meinrado F
MF
Dey
Kaka
K
Choi
Heung-Jin
HJ
Ahn
Youngmi
Y
Sodoma
Andrej
A
Snoeck
Robert
R
Andrei
Graciela
G
De Clercq
Erik
E
Bell
Thomas W
TW
Schols
Dominique
D
D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D016199:Herpesvirus 7, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D000890:Anti-Infective Agents; D015704:CD4 Antigens; D013449:Sulfonamides