An RNA aptamer that interferes with the DNA binding of the HSF transcription activator

Zhao, Xiaoching; Shi, Hua; Sevilimedu, Aarti; Liachko, Nicole F.; Nelson, Hillary C. M.; Lis, John T.

doi:10.1093/nar/gkl470

Cited by 42 publications

(53 citation statements)

References 23 publications

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“…The prototypical example is the Xenopus transcription factor TFIIIA . When DNA-binding proteins are the target of RNA selection, the DNA-binding domain tends to be included in the preferred RNA binding site (Lebruska and Maher 1999;Cassiday and Maher 2001;Huang et al 2003;Choi et al 2006;Zhao et al 2006). Thus, transcription factors implicated in disease pathogenesis may be exploited for the development of therapeutic nucleic acid inhibitors such as RNA aptamers.…”

Section: Summary and Future Prospectsmentioning

confidence: 99%

Selection and characterization of anti-NF-κB p65 RNA aptamers

Wurster¹,

Maher²

2008

RNA

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NF-kB transcription factors include a group of five mammalian proteins that form hetero-or homodimers and regulate hundreds of target genes involved in acute inflammation, HIV-1 transcription activation, and resistance to cancer therapy. We previously used in vitro selection to develop a small RNA aptamer (anti-p50) that binds the DNA-binding domain of NF-kB p50 2 with low nanomolar affinity but does not bind NF-kB p65 2 . Here, we report the in vitro selection of anti-NF-kB p65 RNA aptamers using parallel in vitro selections with either a fully randomized RNA library or a degenerate RNA library based on the primary sequence of the 31-nucleotide anti-p50 RNA aptamer. We report the characterization of these aptamers with respect to NF-kB target specificity, affinity, minimal sequence requirements, secondary structure, and competition with DNA kB sites. These results expand opportunities for artificial inhibition of NF-kB transcription factor dimers containing p65 subunits.

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Section: Summary and Future Prospectsmentioning

confidence: 99%

Selection and characterization of anti-NF-κB p65 RNA aptamers

Wurster¹,

Maher²

2008

RNA

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“…As demonstrated by us and others, RNA aptamers can be a powerful means to modulate transcription factors (Lebruska and Maher, 1999;Fan et al, 2004;Zhao et al, 2006). While most previously characterized RNA aptamers to DNAbinding proteins were found to recognize the DNA-binding surface of the targeted proteins, the aptamers we have selected and characterized here for ERa did not follow this pattern.…”

Section: Discussionmentioning

confidence: 81%

“…Several aptamers isolated previously for transcription factors were shown to interact with their target protein through the DNA binding site or domain and compete with the cognate DNA for binding (Lebruska and Maher, 1999;Fan et al, 2004;Zhao et al, 2006). But this was not the case for AptER-1, whose binding to ERa was not affected by the presence of 8,000-fold of ERE ( Fig.…”

Section: Rna Aptamers Bind Er With High Affinitymentioning

confidence: 92%

In Search of Novel Drug Target Sites on Estrogen Receptors Using RNA Aptamers

Chatakonda²,

Kourtidis³

et al. 2014

Nucleic Acid Therapeutics

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Estrogen receptor a (ERa) is a well-validated drug target for a majority of breast cancers. But the target sites on this receptor are far from exhaustively defined. Almost all ER antagonists in clinical use function by binding to the ligand-binding pocket to occlude agonist access. Resistance to this type of drugs may develop over time, not caused by the change of ERa itself, but by changes in ER associated proteins. This observation is fueling the development of reagents that downregulate ER activity through novel binding sites. However, it is challenging to find general ER antagonists that act independently from other known ER ligands. In this report, we describe the utility of RNA aptamers in the search for new drug target sites on ERa. We have identified three high affinity aptamers and characterized one of them in detail. This aptamer interacted with ERa in a way not affected by the presence or absence of either the steroidal ligands or the estrogen response DNA elements, and effectively inhibited ER-mediated transcriptional activation in a breast cancer cell line. Serving as a novel drug lead, it may also be used to guide the rational chemical synthesis of small molecule drugs or to perform screens of small molecule libraries for those that are able to displace the aptamer from its binding site.

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“…First, aptamers can be displaced by RNA constructs that mimic the viral panhandle structure (23), which is widely believed to be a recognition element for N. Second, many of the aptamers selected in the original study have sequences that resemble portions of the RVFV genome or antigenome by BLAST analysis (23). Finally, a survey of aptamer selections against diverse nucleic acid binding proteins demonstrated that aptamers invariably bound to the bona fide nucleic acid binding region of the protein unless deliberate steps were taken to prevent aptamer binding there (24)(25)(26).…”

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confidence: 99%

Inhibition of Rift Valley Fever Virus Replication and Perturbation of Nucleocapsid-RNA Interactions by Suramin

Ellenbecker

Lanchy

Lodmell

2014

Antimicrob Agents Chemother

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Rift Valley fever virus (RVFV) is an emerging infectious pathogen that causes severe disease in humans and livestock and has the potential for global spread. There are currently no proven safe and effective treatment options for RVFV infection. Inhibition of RNA binding to RVFV nucleocapsid protein (N) represents an attractive antiviral therapeutic strategy because several essential steps in the RVFV replication cycle involve N binding to viral RNA. In this study, we demonstrate the therapeutic potential of the drug suramin by showing that it functions well as an inhibitor of RVFV replication at multiple stages in human cell culture. Suramin has been used previously to treat trypanosomiasis in Africa. We characterize the dynamic and cooperative nature of N-RNA binding interactions and the dissociation of high-molecular-mass ribonucleoprotein complexes using suramin, which we previously identified as an N-RNA binding inhibitor in a high-throughput screen. Finally, we elucidate the molecular mechanism used by suramin in vitro to disrupt both specific and nonspecific binding events important for ribonucleoprotein formation. Rift Valley fever virus (RVFV) is a mosquito-transmitted bunyavirus (genus Phlebovirus) that causes severe disease in humans and ruminant livestock. In humans, disease symptoms can range from a mild flu-like illness to hemorrhagic fever, encephalitis, neurological disorders, and blindness (1). Pregnant livestock are at risk for miscarriage, and high mortality rates among newborn animals have been reported (2-4). RVFV can be transmitted by a diverse set of mosquito species, and outbreaks have been more severe outside the historically defined areas of endemicity of sub-Saharan Africa. The potential for RVFV to cause devastating epidemics worldwide is evidenced by its classification as a category A high-priority disease agent by the National Institute for Allergy and Infectious Diseases (NIAID) (5, 6). There are currently no proven safe and effective treatment options for RVFV-infected people or livestock. Increasing our understanding of the basic molecular virology of this important pathogen represents an essential step toward identification of new drug targets and the development of more efficacious antiviral therapeutic compounds.The single-stranded RNA genome of RVFV is composed of three segments (L, M, and S) that appear circular by electron microscopy due to complementarity between the 5=-and 3=-terminal regions (7). The L segment encodes the RNA-dependent RNA polymerase responsible for transcription and replication of the viral genome. The M segment encodes glycoproteins (Gn and Gc) involved in entry into the host cell and nonstructural proteins NSm and 78-kDa protein (8). The S segment utilizes an ambisense strategy to encode the nucleocapsid (N) and NSs proteins, while the genes of the M and L segments are in the negative sense (9). Among all viral gene products, the importance of N is underscored by its involvement during many stages of the RVFV replication cycle. N is an RNA binding prot...

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An RNA aptamer that interferes with the DNA binding of the HSF transcription activator

Cited by 42 publications

References 23 publications

Selection and characterization of anti-NF-κB p65 RNA aptamers

Selection and characterization of anti-NF-κB p65 RNA aptamers

In Search of Novel Drug Target Sites on Estrogen Receptors Using RNA Aptamers

Inhibition of Rift Valley Fever Virus Replication and Perturbation of Nucleocapsid-RNA Interactions by Suramin

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