Inhibition of an HIV-1 Tat-derived peptide binding to TAR RNA by aminoglycoside antibiotics

Mei, Houng‐Yau; Galan, Adam; Halim, Nadia S.; Mack, David P.; Moreland, D.W.; Sanders, Kathryn B.; Truong, Hoa N.; Czarnik, Anthony W.

doi:10.1016/0960-894x(95)00467-8

Cited by 142 publications

(160 citation statements)

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“…The formation and stoichiometry of the small moleculemacromolecule complexes can be deduced by mass measurement. We have previously demonstrated that ESI-MS experiments examining the Tat-TAR or aminoglycoside-TAR interaction are consistent with solution studies (29,30).…”

Section: Identification Of Three Small Molecule Tat-tar Inhibitorssupporting

confidence: 76%

“…Once the RNA had been identified as the molecular target, we conducted out experiments to reveal the binding characteristics of these inhibitors. Previous competition studies (29)(30)(31) suggested that 1 can complex preferentially to TAR in comparison with other nucleic acids, including (a) tRNA, (b) double-stranded homopolymers of DNA or RNA, and (c) single-stranded RNA. Furthermore, mutations at the bulge or loop domains of TAR seem to have little or no effect on the extent of 1 binding (31).…”

Section: ) Inhibitor 1 Binds To the Lower Stem Region Of Tar Rna Andmentioning

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

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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: Identification Of Three Small Molecule Tat-tar Inhibitorssupporting

confidence: 76%

Section: ) Inhibitor 1 Binds To the Lower Stem Region Of Tar Rna Andmentioning

confidence: 99%

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

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158

140

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“…To date, a few low molecular-weight compounds have been reported that block the Tat·TAR interaction in vitro with inhibition constants in the nano-to micromolar range (Mei et al 1995(Mei et al , 1997Hamy et al 1997Hamy et al , 1998Wang et al 1998;Sannes-Lowery et al 1999;Litovchick et al 2001;Du et al 2002;Lind et al 2002;Blount and Tor 2003;Hwang et al 2003;Davis et al 2004;Murchie et al 2004), some of which have also shown viral inhibition in cellular assays. Among these compounds are a number of amino acid and nucleotide analogs (Mestre et al 1999;Arzumanov et al 2000Arzumanov et al , 2001Mayhood et al 2000;Tamilarasu et al 2000) and aminoglycoside antibiotics (Mei et al 1995;Wang et al 1998;Blount and Tor 2003), which have been shown to effectively compete with Tat for binding to TAR. Studies have also focused on modifying and conjugating small molecules to enhance their specificity for TAR through directed and combinatorial chemical approaches (Hamy et al 1998;Gelus et al 1999;Litovchick et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Ligand-induced changes in 2-aminopurine fluorescence as a probe for small molecule binding to HIV-1 TAR RNA

Bradrick¹,

Marino²

2004

RNA

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“…(1a)) [47] and regulatory domains in the RNA genome of HIV (Fig. (1a)), namely TAR [48] and RRE [49]. Since each of these RNA motifs is a recognition site for a protein (TS itself for the TS 5'-UTR, Tat for TAR, and Rev for RRE), binding of aminoglycosides interferes with the formation of the RNA-protein complex (see above).…”

Section: Definition and Explorationmentioning

confidence: 99%

“…The formation of the Tat-TAR complex and its interactions with small molecule inhibitors have been further studied by electrospray ionization mass spectrometry (ESI-MS) [48,83,84] suggesting that data from gas phase MS experiments may complement solution studies on inhibitor affinities. MS-based methods for studying RNA targets and their interactions with small molecules [85,86] may be promising as techniques have been developed for the screening of multiple RNAs simultaneously against compound mixtures [87].…”

Section: Screening Techniquesmentioning

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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Inhibition of an HIV-1 Tat-derived peptide binding to TAR RNA by aminoglycoside antibiotics

Cited by 142 publications

References 14 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

Ligand-induced changes in 2-aminopurine fluorescence as a probe for small molecule binding to HIV-1 TAR RNA

Rational Drug Design and High-Throughput Techniques for RNA Targets

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