RNA and RNA-Protein Complexes as Targets for Therapeutic Intervention

DeJong, Eric S.; Luy, Burkhard; Marino, John P.

doi:10.2174/1568026023394245

Cited by 37 publications

(22 citation statements)

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“…Dervan and colleagues have been quite successful in designing molecules that target specific sequences in DNA (31), but that technology does not exist for targeting specific RNA structures and sequences. Efforts are currently underway to understand the rules of small molecule-RNA interactions (32,33). To determine whether CUG repeats could be targeted by small molecules we screened a small library of known nucleic acid binding molecules and found that pentamidine and neomycin B bound CUG repeats and could displace MBNL1 in vitro.…”

Section: Discussionmentioning

confidence: 99%

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Warf

Nakamori²,

Matthys³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

235

306

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Myotonic dystrophy (DM) is a genetic disorder caused by the expression (as RNA) of expanded CTG or CCTG repeats. The alternative splicing factor MBNL1 is sequestered to the expanded RNA repeats, resulting in missplicing of a subset of pre-mRNAs linked to symptoms found in DM patients. Current data suggest that if MBNL1 is released from sequestration, disease symptoms may be alleviated. We identified the small molecules pentamidine and neomycin B as compounds that disrupt MBNL1 binding to CUG repeats in vitro. We show in cell culture that pentamidine was able to reverse the missplicing of 2 pre-mRNAs affected in DM, whereas neomycin B had no effect. Pentamidine also significantly reduced the formation of ribonuclear foci in tissue culture cells, releasing MBNL1 from the foci in the treated cells. Furthermore, pentamidine partially rescued splicing defects of 2 pre-mRNAs in mice expressing expanded CUG repeats.alternative splicing ͉ triplet repeats ͉ MBNL1 ͉ muscleblind-like 1 ͉ RNA repeats M yotonic dystrophy (DM) is an autosomal dominant genetic disorder that is characterized by a variety of symptoms. There are 2 types of myotonic dystrophy, type 1 (DM1) and type 2 (DM2). DM1 is linked to a (CTG) n repeat expansion in the 3Ј untranslated region of the DMPK gene, whereas DM2 is linked to a (CCTG) n repeat expansion in intron 1 of the ZNF9 gene. The current model is that the expanded repeats are toxic on the RNA level, where either repeat can form a stable structured RNA that aberrantly interacts with proteins in the nucleus (for review see refs. 1, 2).One proposed molecular mechanism that may account for the disease symptoms is that, upon transcription of the expansions, either the CUG or CCUG repeats sequester RNA binding proteins from their normal cellular functions. The protein MBNL1 (Muscleblind-like 1) has been shown to bind both expanded CUG and CCUG repeats in vitro (3-5), and colocalize with these expanded repeats in vivo (6-10). MBNL1 is an alternative splicing factor and its sequestration leads to the missplicing of multiple pre-mRNAs in DM, which is thought to give rise to many of the symptoms of the disease. In support of this model, it has been shown that the disruption of the MBNL1 gene or expression of CUG repeats in mice causes symptoms and missplicing similar to those seen in DM patients (11)(12)(13)(14). Furthermore, disease symptoms can be rescued and missplicing of many pre-mRNAs can be reversed in mice expressing CUG repeats by overexpression of MBNL1 (15).Aside from the overexpression of MBNL1, another possible approach to overcoming the sequestration of MBNL1 is to identify small molecules that specifically bind the CUG repeats and competitively release the sequestered MBNL1. As a step toward identifying a small molecule therapeutic for DM, a small library of molecules known to bind structured nucleic acid were screened for their ability to disrupt an MBNL1-CUG repeat interaction in vitro. Two molecules were identified that strongly disrupted the complex in vitro. Further testing showed tha...

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Section: Discussionmentioning

confidence: 99%

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Warf

Nakamori²,

Matthys³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

235

306

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“…Structural RNAs and RNPs are attractive targets for therapeutic development (DeJong et al 2002;Goodchild 2004). For example, many of the best antibacterial antibiotics target the ribosome by binding to ribosomal RNA at sites that differ slightly between prokaryotes and eukaryotes (Recht et al 1999;Lynch et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Structural RNAs of known and unknown function identified in malaria parasites by comparative genomics and RNA analysis

Chakrabarti¹,

Pearson²,

Grate³

et al. 2007

RNA

115

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As the genomes of more eukaryotic pathogens are sequenced, understanding how molecular differences between parasite and host might be exploited to provide new therapies has become a major focus. Central to cell function are RNA-containing complexes involved in gene expression, such as the ribosome, the spliceosome, snoRNAs, RNase P, and telomerase, among others. In this article we identify by comparative genomics and validate by RNA analysis numerous previously unknown structural RNAs encoded by the Plasmodium falciparum genome, including the telomerase RNA, U3, 31 snoRNAs, as well as previously predicted spliceosomal snRNAs, SRP RNA, MRP RNA, and RNAse P RNA. Furthermore, we identify six new RNA coding genes of unknown function. To investigate the relationships of the RNA coding genes to other genomic features in related parasites, we developed a genome browser for P. falciparum (http://areslab.ucsc.edu/cgi-bin/hgGateway). Additional experiments provide evidence supporting the prediction that snoRNAs guide methylation of a specific position on U4 snRNA, as well as predicting an snRNA promoter element particular to Plasmodium sp. These findings should allow detailed structural comparisons between the RNA components of the gene expression machinery of the parasite and its vertebrate hosts.

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“…[12][13][14] Beside ribozymes, RNA antisense, and RNA interference techniques, [15][16][17][18] RNA targeting using low-molecular weight compounds represents a young but dynamic field. 19,20 Today, only a few systems are used as models for the study of the molecular recognition of drugs by RNA molecules, 21,22 with the design of rational drugs as the ultimate goal. 23 Particularly, aminoglycoside antibiotics form the most studied family of RNA binding drugs.…”

Section: Introductionmentioning

confidence: 99%

Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes: An analysis of x‐ray crystal structures

2003

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The potential of RNA molecules to be used as therapeutic targets by small inhibitors is now well established. In this fascinating wide-open field, aminoglycoside antibiotics constitute the most studied family of RNA binding drugs. Within the last three years, several x-ray crystal structures were solved for aminoglycosides complexed to one of their main natural targets in the bacterial cell, the decoding aminoacyl-tRNA site (A site). Other crystallographic structures have revealed the binding modes of aminoglycosides to the three existing types of resistance-associated enzymes. The present review summarizes the various aspects of the molecular recognition of aminoglycosides by these natural RNA or protein receptors. The analysis and the comparisons of the detailed interactions offer insights that are helpful in designing new generations of antibiotics.

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RNA and RNA-Protein Complexes as Targets for Therapeutic Intervention

Cited by 37 publications

References 0 publications

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Pentamidine reverses the splicing defects associated with myotonic dystrophy

Structural RNAs of known and unknown function identified in malaria parasites by comparative genomics and RNA analysis

Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes: An analysis of x‐ray crystal structures

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