Laboratory of XNA Screening and Design
|Visiting Project Leader||Satoshi Obika|
|Sub-Project Leader||Yuuya Kasahara|
|Research Scientist||Hidekazu Hoshino|
|Research Assistant||Chizuko Kameoka
|Administrative Assistant||Yoriko Ninomiya
|Graduate Student||Hao Ding
|Research Trainee||Takumi Okuda
2. Background and objectives
In recent years, artificial nucleic acid (Xeno nucleic acid; XNA) developed by chemical technology has served as a medicine. For example, the antisense nucleic acid "Kynamro" which has already been approved by the FDA in the USA is a nucleic acid drug, which targets mRNA and shows a drug effect by controlling the translation to a protein causative of disease. In addition, the nucleic acid aptamer "Macugen" which is also approved by the PMDA in the JPN is a nucleic acid drug, which controls the activity by binding to the causative protein. As described above, there are various types of nucleic acid drug, and it is possible to target in vivo molecules such as DNA, RNA and protein. Therefore, nucleic acid drug leads to the development of a specific drug for intractable diseases that are difficult to treat with existing methods. In this project, synthesis of XNA to be introduced into nucleic acid drug such as antisense nucleic acid and nucleic acid aptamer, and screening of sequence, and target specific nucleic acid is isolated. In addition, we aim to create practical nucleic acid drugs by designing and optimizing the isolated hit molecules according to the application.
3. Overview of our research
High-performance antisense nucleic acids require characteristics such as binding affinity for target RNA, in vivo stability, intracellular migration and safety. Likewise, for high-performance nucleic acid aptamers, in vivo stability, safety, binding affinity to target proteins, inhibitory activity, and retention in the body are important. In this project, we are developing XNA that modified the base part, sugar part, phosphoric acid part of nucleic acid to contain the above characteristics. On the other hand, we are aiming to create nucleic acid drugs that can control the place and timing of medicinal effects as desired. For example, we are developing XNAs whose structure and properties change according to the surrounding environment. Then, we can expect further improvement of drug efficacy and reduction of dosage and side effects of nucleic acid drug. We are also developing new screening methods that can efficiently screen active sequences from candidate sequence libraries. Especially in screening of nucleic acid aptamers, we are developing polymerase mutants that can extend XNAs. In this way, we conduct research aiming at the development of nucleic acid drug for various diseases including intractable rare diseases by consistently doing from synthesis of artificial nucleic acid to screening.