The sequence-specific cleavage of RNA by artificial chemical ribonucleases

Based on work spanning 50 years, several groups have recently achieved the specific cleavage of RNA by attaching RNA-cleaving chemical moieties to antisense oligonucleotides. Such artificial chemical ribonucleases have potential as a possible next generation of antisense compounds and also as probes for structural and functional investigations of RNA. Different chemical moieties, such as polyamines, imidazoles, and metal complexes, have been used as the catalytic part of the artificial nucleases. To be of practical use as therapeutics, however, the conjugates must fulfil a number of strict requirements, such as ease of preparation, chemical stability, selectivity, nontoxicity, and, for metal complexes, inertness to loss of cation from the ligand. In addition, high cleavage efficiency is essential to overcome short lifetimes of cellular mRNA targets, and the reaction should not depend on additional cofactors. Based on these criteria, we believe that metal complexes, in particular macrocyclic lanthanide complexes, have the best chance of success for said purpose.