An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication

Hamy, François; Felder, E.; Heizmann, Gerhard; Lazdins, Janis; Aboul‐ela, Fareed; Varani, Gabriele; Karn, Jonathan; Klimkait, Thomas

doi:10.1073/pnas.94.8.3548

Cited by 249 publications

(229 citation statements)

References 25 publications

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“…Although this region is not required for Tat binding (14)(15)(16), it is likely that small molecule loop binders can still interfere with Tat binding through an allosteric mechanism. The fact that 3 binds to the loop region and inhibits Tat-TAR binding provides encouragement for discovering ligands that bind to any loop-containing RNA molecules.…”

Section: (3) Inhibitor 3 Inhibits the Tat-tar Interaction By Binding mentioning

confidence: 99%

“…While U 23 of the bulge serves as the marker for Tat recognition, the hairpin loop provides a homing site for other cellular proteins (12). Both are important for the formation of processive transcription complexes through specific protein-RNA interactions (14)(15)(16). Deletion of either bulge or loop residues of TAR impairs the transcription and, subsequently, the replication of HIV-1 (5,12).…”

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confidence: 99%

“…A segment of HIV-1 mRNA (residues 1-59), identified as the transactivation responsive element (TAR), adopts a stem-loop secondary structure consisting of a highly conserved hexanucleotide loop and a three-nucleotide bulge flanked by two doublestranded stems (12,13). HIV-1 encodes a regulatory protein, Tat, for interacting with TAR and activating both the initiation and elongation processes of transcription (14)(15)(16). While U 23 of the bulge serves as the marker for Tat recognition, the hairpin loop provides a homing site for other cellular proteins (12).…”

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confidence: 99%

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Inhibitors of Protein−RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules

Mei¹,

Cui²,

Heldsinger³

et al. 1998

Biochemistry

159

140

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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. Drug discovery has traditionally involved a search for inhibitors of protein complexation to small molecules (e.g., substrates or ligands) or macromolecules (e.g., other proteins, nucleic acids, or polysaccharides). While agonists or antagonists of macromolecular receptors that become useful drugs must display a wide range of other attributes, including the appropriate physicochemical properties, pharmacokinetic and pharmacodynamic properties, stability, etc., they must first be protein ligands. The vast majority of available drugs act by binding noncovalently to a protein, preventing or (less often) stimulating that protein's complexation to a complement (1).Complexes of nucleic acid and proteins are key intermediates in all transcriptional and translational processes. Some nucleic acids (e.g., ribozymes) even form functional complexes with small molecules (2). Nonetheless, nucleic acids are widely viewed as ineffective targets for the discovery of low-molecular weight inhibitors. One reason is that the linear motif in single-stranded DNA and the repetitive motif in double-stranded DNA provide attractive targets for large, linear binding molecules (3), but unattractive targets for the small molecules that lead to orally available medications. Another reason is that the lack of tertiary structure in DNA does not afford the diverse topology associated with folded proteins.However, single-stranded RNA often folds into welldefined tertiary structures (4). Furthermore, such structures serve as docking sites for transcriptional activators (5) and substrates for self-splicing reactions (6, 7). Can such structured nucleic acids display sufficient shape diversity to permit the complexation of a small molecule at one site in a virtual sea of nucleic acid material? This is the essential question whose presumed negative answer hinders drug discovery at the nucleic acid level.Certain cis-acting RNA elements are essential for the gene expression of human immunodeficiency virus type 1 (HIV-1) (8). The functions and sequences of these RNA molecules have been well characterized (9-11). A segment of HIV-1 mRNA (residues 1-59), identified as the transactivation responsive element (TAR), adopts a stem-loop secondary structure consisting of a highly cons...

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Section: (3) Inhibitor 3 Inhibits the Tat-tar Interaction By Binding mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Inhibitors of Protein−RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules

Mei¹,

Cui²,

Heldsinger³

et al. 1998

Biochemistry

159

140

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“…There are many potential RNA targets, including RNA that is involved in cellular proteins interaction such as transcription, splicing, and translation and, RNA that is involved in viral infection such as human immunodeficiency virus (HIV). Several systematic screens have been performed against fragments of the HIV-1 genomic RNA, but in all cases, the high affinity hits were strongly cationic [1][2][3] and their recognition was dominated by electrostatic effects that are often poorly selective. There is thus a need for strategies based on high selectivity rather than on high affinity.…”

Section: Introductionmentioning

confidence: 99%

NMR-based identification of peptides that specifically recognize the d-arm of tRNA

2005

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“…Combinatorial approaches have been used to identify peptoids able to specifically inhibit the interaction of TAR with Tat and to display antiviral properties in tissue culture (Hamy et al, 1997(Hamy et al, , 1998. Alternatively, oligonucleotides can be evaluated as RNA ligands.…”

Section: Introductionmentioning

confidence: 99%

Modulating viral gene expression by aptamers to RNA structures

Toulmé

Darfeuille

Kolb

et al. 2003

Biology of the Cell

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Oligonucleotides exhibiting a strong affinity and a high specificity for RNA hairpins were obtained by in vitro selection. Such oligomers give rise to loop-loop complexes with the target hairpins: the trans-activation responsive (TAR) element of the Human Immunodeficiency virus-1 (HIV-1) or subdomains of the Hepatitis C virus (HCV) mRNA. Chemically modified derivatives of an antiTAR aptamer were shown to compete out the binding of the viral protein Tat and to selectively inhibit the in vitro TAR-dependent transcription of a reporter gene. In addition, antisense oligomers derived from sequences selected against the domain IIId of the HCV internal ribosome entry site were shown to specifically block translation both in a cell-free assay and in cultured cells.

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An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication

Cited by 249 publications

References 25 publications

Inhibitors of Protein−RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules

Inhibitors of Protein−RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules

NMR-based identification of peptides that specifically recognize the d-arm of tRNA

Modulating viral gene expression by aptamers to RNA structures

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