Abstract
TAR RNA represents an attractive target for the intervention of human immunodeficiency virus type 1 (HIV-1) replication by small molecules. We now describe three small molecule inhibitors of the HIV-1 Tat-TAR interaction that target the RNA, not the protein. The chemical structures and RNA binding characteristics of these inhibitors are unique for each molecule. Results from various biochemical and spectroscopic methods reveal that each of the three Tat-TAR inhibitors recognizes a different structural feature at the bulge, lower stem, or loop region of TAR. Furthermore, one of these Tat-TAR inhibitors has been demonstrated, in cellular environments, to inhibit (a) a TAR-dependent, Tat-activated transcription and (b) the replication of HIV-1 in a latently infectious model.
MeSH terms
-
Allosteric Regulation / drug effects
-
Allosteric Regulation / genetics
-
Aminoglycosides
-
Anti-Bacterial Agents / pharmacology
-
Anti-HIV Agents / metabolism
-
Anti-HIV Agents / pharmacology*
-
Binding, Competitive / drug effects
-
Binding, Competitive / genetics
-
Down-Regulation / drug effects
-
Down-Regulation / genetics
-
Drug Design
-
Gene Products, tat / antagonists & inhibitors
-
Gene Products, tat / metabolism
-
HIV Long Terminal Repeat / drug effects*
-
HIV-1 / drug effects
-
HIV-1 / genetics*
-
HIV-1 / physiology
-
Humans
-
Quinazolines / pharmacology
-
Quinoxalines / pharmacology
-
RNA, Viral / antagonists & inhibitors*
-
RNA, Viral / metabolism
-
RNA-Binding Proteins / antagonists & inhibitors*
-
RNA-Binding Proteins / metabolism
-
Transcriptional Activation / drug effects
-
Virus Replication / drug effects
-
Virus Replication / genetics
-
tat Gene Products, Human Immunodeficiency Virus
Substances
-
Aminoglycosides
-
Anti-Bacterial Agents
-
Anti-HIV Agents
-
Gene Products, tat
-
Quinazolines
-
Quinoxalines
-
RNA, Viral
-
RNA-Binding Proteins
-
tat Gene Products, Human Immunodeficiency Virus
-
2,4-diaminoquinazoline