Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.4 (RNase H)
 2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antisense oligonucleotides (ON) allow the specific control of gene expression and phosphorothioate derivatives are currently being evaluated for possible clinical applications. Numerous second generation ON analogues with improved pharmacological properties have been described. Most of them, however, do not recruit RNase H, which is known to increase ON potency by eliciting the specific degradation of the target RNA. Silverman, Torrence and colleagues have conjugated 2,5A to natural antisense ON and demonstrated the preferential cleavage of a target RNA in cell-free and intact cell experiments. We have established for the first time that RNase H-incompetent ON, viz. alpha-anomeric ON analogues, can be converted into sequence-specific nucleases upon conjugation to 2,5A. The use of alpha-ON- and beta-ON-2,5A chimeras has allowed us to delineate the part played by RNase H and RNase L in target RNA degradation and translation arrest. Finally, the present studies have revealed limitations which are encountered in the choice of a suitable target for such ON-2,5A chimeras.
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PMID:Selective mRNA degradation by antisense oligonucleotide-2,5A chimeras: involvement of RNase H and RNase L. 986 93

2',5'-Oligoadenylate (2-5A) antisense chimeric oligonucleotides were synthesized containing varying 2'-O-methyl-ribonucleotide substitution patterns in the antisense domain. The ability of these composite oligonucleotides to mediate RNase H- and RNase L-catalyzed RNA degradation showed that these two enzymes have different activation requirements.
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PMID:Discrimination between ribonuclease H- and ribonuclease L-mediated RNA degradation by 2'-O-methylated 2-5A-antisense oligonucleotides. 1023 Jun 38

Recent work has demonstrated that the activity of a ubiquitous cellular enzyme, ribonuclease L (RNase L), can be harnessed to cleave targeted RNA species. Activation of RNase L is dependent on the presence of 2',5'-linked oligoadenylates (2-5A), usually produced by cells infected with viruses. By conjugating synthetic 2-5A to specific antisense compounds, it is now possible to selectively degrade RNAs in an RNase L-dependent manner, thereby providing an alternative to RNase H-dependent approaches. In this summary, we provide an updated description of the synthesis procedure for constructing these chimeric 2-5A antisense molecules. Examples of successful applications of the 2-5A antisense strategy are described, along with some of the procedures involved in those studies. Several methods are also provided for optimizing compound uptake and analyzing their effects on cells. Finally, we discuss the current body of evidence that supports the contention that RNase L is indeed the primary mediator of 2-5A antisense effects and the possible implications that this has on the future of this therapeutic approach.
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PMID:Controlling gene expression with 2-5A antisense. 1045 83