A New Class of HIV-1 Tat Antagonist Acting through Tat−TAR Inhibition

Hamy, François; Brondani, Vincent; Flörsheimer, Andreas; Stark, Wilhelm; Blommers, Marcel J. J.; Klimkait, Thomas

doi:10.1021/bi972947s

Cited by 145 publications

(126 citation statements)

References 45 publications

(78 reference statements)

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“…Under similar conditions, modifications at guanine residues 21, 26, 28, and 32-34, or at C 24 in the bulge region, were not affected by the presence of 3. At higher concentrations, e.g., [3] ) 500 µM, some (∼30%) secondary protection was found for G 26 and G 28 , both located in the upper stem region. Interestingly, guanine residues in the loop region were not protected by 3 under any condition.…”

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

confidence: 97%

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

157

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: 97%

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

157

140

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“…The concept of combining positively charged anchor groups for contacts with the RNA backbone, as they are provided by the ammonium substituents in aminoglycosides, with a flat aromatic moiety for stacking interactions has been realized in the modular In-PRiNts ("inhibitor of protein-ribonucleotide sequences") [106]. …”

Section: Rational Design and Combina-torial Synthesis Of Rna Bindersmentioning

confidence: 99%

Rational Drug Design and High-Throughput Techniques for RNA Targets

Hermann

Westhof²

2000

CCHTS

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RNA molecules are the only known molecules which possess the double property of being depository of genetic information, like DNA, and of displaying catalytic activities, like protein enzymes. RNA molecules intervene in all steps of gene expression and in many other biological activities. Like proteins, RNAs achieve those biological functions by adopting intricate three-dimensional folds and architectures. Further, as in protein sequences, RNA sequences contain signatures specific for threedimensional motifs which participate in recognition and binding. In regulatory pathways, RNA molecules exist in equilibria between transient structures differentially stabilized by effectors such as proteins or cofactors. Therefore, RNA molecules display their potential as drug targets on different levels, namely in three-dimensional folds, in structural equilibria and in RNA-protein interfaces. Several examples will be described together with the already available techniques for combinatorial synthesis and high-throughput screening of potential drug and target RNA molecules.

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“…9,9-Bis-(5,5-Dimethyl-2-oxo-2-λ 5 -[1,3,2]dioxaphosphinan-2-yl) 9,10-dihydro-acridine (11). 6.10; N, 2.84%. This compound was crystallized from acetonitrile (2 mL).…”

mentioning

confidence: 95%

“…Acridine derivatives have numerous applications 1 that include biological fluorescent/ chemiluminiscent probes 2,3 as well as anti-tumor, 4 anti-bacterial, 5 anti-HIV, 6 antimalarial, 7 and DNA-binding agents.…”

Section: Introductionmentioning

confidence: 99%

Facile formation of phosphono-acridanes via chloroacridines

Srinivas¹,

Swamy²

2009

Arkivoc

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Novel bis-phosphonates bearing an acridane moiety are readily synthesized by the simple reaction of appropriate 9-chloroacridines with phosphites of the type (RO) P(O)H. The by-product acridones could be converted back to the chloroacridines by treating them with thionyl chloride, and thus the effective yield is high. The structures of three bis-phosphonates are confirmed by X-Ray crystallography.2

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A New Class of HIV-1 Tat Antagonist Acting through Tat−TAR Inhibition

Cited by 145 publications

References 45 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

Rational Drug Design and High-Throughput Techniques for RNA Targets

Facile formation of phosphono-acridanes via chloroacridines

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