Recently, nucleic acid medicines attract much attention as a next generation of drug targeting messenger RNA (mRNA) and/or microRNA (miRNA). To develop nucleic acid medicine, artificial nucleic acids (XNAs) that can recognize DNA and RNA in a sequence-specific manner with sufficient nuclease resistivity and low toxicity are necessary. Previous nucleic acid medicines have been designed by utilizing XNAs that involve modified ribose as a scaffold of natural four nucleic acids. Although these XNAs can recognize DNA and RNA with high affinity, nuclease resistivity was not sufficient in the serum because their scaffolds were similar to natural DNA and RNA. In addition, further modification of these XNAs with functional molecules were difficult because available modification sites were already capped. Hence, new XNAs that can overcome these limitations were required for designing still more effective nucleic acid medicines.
Previously, our group has successfully developed a series of XNAs that are composed of acyclic serinol derivatives as new scaffolds of nucleobases. Among them, serinol nucleic acid (SNA) and acyclic L-threoninol nucleic acid (L-aTNA) formed stable duplex particularly with natural RNA. The affinity of SNA and L-aTNA towards RNA was much higher than that of natural DNA. Our group has applied SNA to modification of siRNA, and found that siRNA modified with SNA at the termini showed remarkable nuclease resistivity, increase in the activity toward target RNA, and improved strand selectivity to guide strand. Furthermore, ant-microRNA oligonucleotide (AMO) composed of only SNA could block miRNA (miR21). It should be noted that its AMO activity was higher than commercially available AMO of bridged (locked) nucleic acid (BNA/LNA).
On the bases of these results, we propose to design nucleic acid medicine by use of XNAs composed of acyclic serinol derivatives (SNA and L-aTNA). Our proposal involves following four sections; 1) expansion of functionalities of SNA and L-aTNA by chemical modification, 2) design of modified siRNA that suppresses cell growth of pancreas cancer, 3) design of modified antisense oligonucleotide and siRNA for the therapy of diabetic kidney disease, 4) design of modified anti-microRNA oligonucleotide and antisense oligonucleotide targeting microRNA (miR21 and miR164a) to suppress inflammatory response. By this project, we can establish fundamental technology of acyclic XNAs for designing nucleic acid medicines.
Figure 1: Chemical structures of three acyclic nucleic acids, D-aTNA (acyclic, D-Threoninol Nucleic Acid), SNA (Serinol Nucleic Acid), and L-aTNA developed by our group (upper panel), and hybridization properties among each (artificial) oligonucleotide (lower panel). 
Figure 2: DNA and XNA synthesizer (and my students)Any oligonucleotide can be easily synthesized by designing the sequence on the computer of DNA and XNA synthesizer that equips glass bottles involving (artificial) nucleotide monomer solutions and reagents.
Figure 3: Visualization of mRNA in cell by use of molecular beacon composed of totally SNA.SNA and L-aTNA have higher affinity towards RNA than DNA does. Furthermore, since their backbone structures are entirely different from ribose scaffold, they are sufficiently stable in cell due to high nuclease resistivity. Hence, they are suitable for the recognition of RNA in cell.