DNA and RNA have significance as genetic materials, therapeutic potential, and supramolecular properties. Advances in nucleic acid chemistry have enabled large-scale synthesis of DNA and RNA oligonucleotides and oligomers of non-natural nucleic acids, including artificial nucleic acids (xeno nucleic acids; XNAs) with non-ribose scaffolds. In this feature article, we review the chemical structures of XNAs with non-ribose scaffolds, their hybridization abilities, and their unique behaviors with a particular focus on the acyclic XNAs. First, we overview XNAs with non-ribose cyclic scaffolds and then those with acyclic scaffolds by focusing on their hybridization abilities with themselves and with DNA and RNA, and discuss the unexpectedly stable homo-duplex formation of acyclic XNAs. Next, we shed light on our acyclic threoninol nucleic acid (aTNA) and serinol nucleic acid (SNA) and show their helical preferences based on their chirality, then orthogonal control of hybridization and helical amplification of achiral XNAs are demonstrated. Finally, we show non-enzymatic template-directed synthesis of L-aTNA, and the creation of an artificial genetic system with XNAs with non-ribose scaffolds is described as a future prospect.

Evolution of xeno nucleic acid (XNA) world essentially requires template-directed synthesis of XNA polymers. In this study, we demonstrate template-directed synthesis of an acyclic XNA, acyclicl-threoninol nucleic acid (l-aTNA), via chemical ligation mediated by N-cyanoimidazole. The ligation of an l-aTNA fragment on an l-aTNA template is significantly faster and occurs in considerably higher yield than DNA ligation. Both l-aTNA ligation on a DNA template and DNA ligation on an l-aTNA template are also observed. High efficiency ligation of trimer l-aTNA fragments to a template-bound primer is achieved. Furthermore, a pseudo primer extension reaction is demonstrated using a pool of random l-aTNA trimers as substrates. To the best of our knowledge, this is the first example of polymerase-like primer extension of XNA with all four nucleobases, generating phosphodiester bonding without any special modification. This technique paves the way for a genetic system of the l-aTNA world.