Laboratory of Drug Discovery, Center for Research and Education on Drug Discovery

Research

3. Pharmaceutical chemistry using nucleic acid

In addition to conventional small molecule drugs, large molecule drugs (biological drugs) mainly dealing with antibody have been widely used. They have conducted a number of clinical experiments on nucleic acid drugs, which is going to (or be supposed to be) another main component. However, only three of them have been on the market (as of April, 2015). Nucleic acid drugs have so many problems as 1) in vivo nuclease resistance 2) thermal stability with the targets 3) escape from innate immune response. To solve these problems, it is required to develop artificial nucleic acid that adds chemical modification into nucleobase, sugar, and phosphate moieties as new pharmaceutical materials. For the purpose, it is necessary to understand the structure and nature of targeting nucleic acid and protein, and to pursue the adequate "molecular design" and "organic chemistry" for synthesis of aiming artificial nucleic acids.

For example, Apio nucleic acid, which was synthesized in our laboratory, is a structural isomer of DNA, and it has high nuclease resistance. It is artificial nucleic acid that is capable of complete modified extension by DNA polymerase. It is expected to become development to an aptamer.

We also succeeded in the development of reaction to dumbbell DNA from double strand at the same time, using a trivalent azide reagent. The reagent is useful to combine duplex with label or targeting molecule because the resulting dumbbell DNA has a modifiable azide more.

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