Non-natural nucleosides for the specific recognition of Watson-Crick base pairs

The specific recognition of any given DNA sequence by ligands is expected to revolutionize medicine and biotechnology in the future. Using oligonucleotides as sequence-specific ligands to form triple helical structures offers a particularly attractive approach due to their availability and their simple recognition code based mainly on directional hydrogen bond contacts. However, the recognition code is limited to only two out of four Watson-Crick base pairs in DNA and only homopurine sequences can be effectively targeted by triplex-forming oligonucleotides at present. In order to overcome this limitation much effort has been directed in the past to the development of novel nucleoside analogs capable of binding any given base pair. This review will summarize the different structural approaches to achieve mixed base pair recognition and try to evaluate the various contributions to binding.