Expansion of Genetic Alphabets: Designer Nucleobases and Their Applications

Living things use the DNA/RNA composed of naturally occurring nucleic acids to store, retrieve, and transmit their genetic data. However, with only four naturally occurring nucleic acids (namely A,T/U,G and C), the genetic information capacity, and chemical variety of DNA and RNA gets limited. Deoxyribose/ribose-phosphate backbones also constrain DNA and RNA characteristics and have poor chemical and physiological stability, which significantly restricts DNA and RNA's practical applications. Over the years, extensively modified nucleobase pairs with novel base-pairing properties have been synthesized. Such nucleobases have been used towards designing and synthesizing DNA and RNA analogs containing an expanded genetic alphabet with tailored functional properties. Recent developments in the production of synthetic unnatural base pairs are paving the way for xenobiology research and genetic alphabet expansion technology. In this review, we herein describe the brief history towards development of several hydrogen and non-hydrogen bonded unnatural base pairs and their applications. We also highlight our own works in the design and synthesis of a new class of triazolyl unnatural nucleosides which offer a unique Charge Transfer (CT) Complexation force to stabilize a DNA Duplex when incorporated into short oligonucleotide sequences.