Molecular mechanisms of action of antisense drugs

Given the progress reported during the past decade, a wide range of chemica l modifications may be incorporated into potential antisense drugs. These m odifications 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 cha racterized. A number of mechanisms other than RNase H have also been report ed for non-DNA-like antisense drugs. For example, activation of splicing, i nhibition of 5'-cap formation, translation arrest and activation of double strand RNases have all been shown to be potential mechanisms. Thus, there i s a growing repertoire of potential mechanisms of action from which to choo se, and a range of modified oligonucleotides to match to the desired mechan ism. Further, we are beginning to understand the various mechanisms in more detail. These insights, coupled with the ability to rapidly evaluate activ ities of antisense drugs under well-controlled rapid throughput systems, su ggest that we will make more rapid progress in identifying new mechanisms, developing detailed understanding of each mechanism and creating oligonucle otides that better predict what sites in an RNA are most amenable to antise nse drugs of various chemical classes. (C) 1999 Elsevier Science B.V. All r ights reserved.