Blocking HIV replication by targeting Tat protein.
BACKGROUND
A rapid development of viral drug resistance poses a serious limitation in the current drug development programs against HIV. In turn, this obstacle forms the basis for new efforts, which utilize alternative viral targets.


RESULTS
By aiming at the Tat-driven process of HIV gene regulation, we discovered a new class of compounds as well as a novel target. The candidate compound acts on the one hand by classically inhibiting Tat/TAR complexation, however, without binding to nucleic acids.


CONCLUSIONS
Structure and molecular modeling/dynamics suggest that the stilbene derivative CGA137053 directly binds to Tat protein but not TAR RNA. As a completely new, second property, the compound also antagonizes a TAR-independent activity of free Tat protein by preventing the recently described upregulation of the HIV coreceptor CXCR4. With the stilbene CGA137053, we have identified a potent, double-hitting and chemically feasible Tat antagonist. The compound possesses high target specificity and low cytotoxicity, is not restricted to the Tat/TAR axis of HIV inhibition and highly active on HIV-infected, primary human cells.
Hamy
F
F
Novartis Pharma Research, Basel, Switzerland.
Gelus
N
N
Zeller
M
M
Lazdins
J L
JL
Bailly
C
C
Klimkait
T
T
D000577:Amides / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008214:Lymphocytes / Q000821:virology; D008264:Macrophages / Q000821:virology; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D000577:Amides; D019380:Anti-HIV Agents; C415764:CGA 137053; D015696:Gene Products, tat; D007093:Imidazoles; D012367:RNA, Viral; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D001616:beta-Galactosidase