Design of triplex-forming oligonucleotides for binding DNA and RNA: Optimizing affinity and selectivity

Recent progress in the design of oligonucleotides as ligands for binding specific sequences of DNA and RNA is described, Many recent studies in the design of oligonucleotides have focused on modification of the backbone and/or bases in DNA; however, it is shown here that many desirable properties, such as affinity, sequence selectivity, and resistance to degradation, can be greatly improved without modification of backbone or bases but rather, by topological modification of DNA structure, A major new approach to increasing affinity and selectivity is the targeting of single stranded nucleic acids by tripler formation, This involves the topological modification of linking two binding domains; one such strategy is to construct them in circular form. Cyclic DNA oligonucleotides can bind target DNA and RNA strands with much higher affinity and sequence selectivity than standard Watson-Crick complements. These advances in oligonucleotide design may lead to useful strategies for medical diagnostic sequence recognition, and potentially for inhibition of specific disease-related genes.