Molecular mechanisms of action of antisense drugs.
Given the progress reported during the past decade, a wide range of chemical modifications may be incorporated into potential antisense drugs. These modifications may influence all the properties of these molecules, including mechanism of action. DNA-like antisense drugs have been shown to serve as substrates when bound to target RNAs for RNase Hs. These enzymes cleave the RNA in RNA/DNA duplexes and now the human enzymes have been cloned and characterized. A number of mechanisms other than RNase H have also been reported for non-DNA-like antisense drugs. For example, activation of splicing, inhibition of 5'-cap formation, translation arrest and activation of double strand RNases have all been shown to be potential mechanisms. Thus, there is a growing repertoire of potential mechanisms of action from which to choose, and a range of modified oligonucleotides to match to the desired mechanism. Further, we are beginning to understand the various mechanisms in more detail. These insights, coupled with the ability to rapidly evaluate activities of antisense drugs under well-controlled rapid throughput systems, suggest that we will make more rapid progress in identifying new mechanisms, developing detailed understanding of each mechanism and creating oligonucleotides that better predict what sites in an RNA are most amenable to antisense drugs of various chemical classes.
Crooke
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Isis Pharmaceuticals Inc, Carlsbad, CA 92008, USA.
D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D015195:Drug Design; D006801:Humans; D009693:Nucleic Acid Hybridization / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000235:genetics; D016337:RNA, Catalytic / Q000378:metabolism; D016914:Ribonuclease H / Q000378:metabolism; D013379:Substrate Specificity / Q000235:genetics
D016376:Oligonucleotides, Antisense; D016337:RNA, Catalytic; D012313:RNA; D016914:Ribonuclease H