CADA, a potential anti-HIV microbicide that specifically targets the cellular CD4 receptor.
The cyclotriazadisulfonamide (CADA) compounds are a new class of specific CD4-targeted HIV entry inhibitors. The in vitro anti-HIV activity of CADA was shown to correlate with its ability to specifically downmodulate cell surface expression of the CD4 receptor in human cells. Here, we evaluated its potential as an anti-HIV microbicide. CADA exerted a clear CD4 receptor downregulating effect in dendritic cells (DC) and subsequently inhibited HIV-1(BaL) replication in DC/T cell co-cultures. The compound proved to be active against a variety of clinical isolates belonging to the HIV-1 subtypes A, B, C, D, F, G, H, AE and O. Furthermore, it prevented human T cells from being infected with the laboratory-adapted strains X4 HIV-1(NL4.3) and R5 SIV(mac251). Flow cytometric analysis demonstrated a significant and dose-dependent downregulation of CD4 on macaque PBMCs. In addition, the compound exerted a marked anti-SIV(mac251) activity in these cells from simian origin. The combination of CADA with cellulose acetate phthalate (CAP) resulted in a synergistic inhibition of HIV-1 and SIV infection. Finally, gel formulated CADA proved to preserve the CD4 downmodulating and antiviral activity of this compound when formulated as a microbicide gel. Thus, our data suggest that CADA may have potential as a broad-spectrum anti-HIV microbicide drug candidate. The preservation of the activity of gel formulated CADA will make it now feasible for testing this unique entry inhibitor in non-human primates, not only as a single drug but also in a synergistic conjunction with other anti-HIV compounds.
Vermeire
Kurt
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. kurt.vermeire@rega.kuleuven.be
Brouwers
Joachim
J
Van Herrewege
Yven
Y
Le Grand
Roger
R
Vanham
Guido
G
Augustijns
Patrick
P
Bell
Thomas W
TW
Schols
Dominique
D
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002482:Cellulose / Q000031:analogs & derivatives / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000821:virology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D053586:Virus Internalization / Q000187:drug effects
C498074:9-benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododeane; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D006571:Heterocyclic Compounds; D002482:Cellulose; C011708:cellulose acetate phthalate