TAKEHIKO WADA

TOHOKU UNIVERSITY

Institute of Multidisciplinary Research for Advanced Materials (IMRAM)

Advanced Research Center for Innovations in Next Generation Medicine (INGEM)

Professor

About

Prof. Takehiko WADA's research interests focus on Chemical Biology, Nucleic Acids Chemistry, Oligonucleotide Therapeutics, and Supramolecular Asymmetric Photochirogenesis and has published more than 250 scientific papers and books and is a member of a Chemical Researcher of the JSPS from 2018, and President of Japan Society of Nucleic Acids Chemistry (JSNAC).

Research Disciplines

Chemical Biology, Medicinal Chemistry, Nucleic Acids Chemistry

Featured Presentation

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Title: Rational Design of Next-Generation Nucleic Acid Medicines with High Therapeutic Potencies and Target Cell Selectivity

Keywords: Nucleic Acid Medicines, Cancer Therapy, Target RNA Cleavage, Peptide Nucleic Acids, Rational Design, Thermodynamic Parameters

Abstract: We have recently proposed a new strategy and a practical tool for cancer cell-selective oligonucleotide therapeutics, named Peptide Ribonucleic Acids (PRNAs), with active on-off control of functional RNA activities corresponding to cancer cell-specific intracellular conditions. The PRNAs can be actively off to on switching the complexation behaviour with target RNAs induced by the lowered pH of cancer’s cytoplasm.

Meanwhile, RNase H activities of antisense molecules would be one of the most crucial factors for a practical antisense strategy. Thus, in this study, we have been designed PRNA-DNA chimeras, in which both PRNA and DNA domains work as recognition sites for the complexation with target RNAs and PRNA moieties work as recognition control/switching devices, while DNA-RNA hybrids formed in the DNA domains of the chimera should be substrates of RNase H and then target RNAs cleaved by the enzyme. To improve cleavage efficiency, we focused on the binding mechanism of DNA/RNA duplex to RNase H’s cationic binding channel and proposed a chimeric neutral amide backbone of PRNA connected with negatively charged DNA’s phosphate-sugar backbone. In the design, the cleavage site of the target RNA should be restricted to the position of the junction site of the chimera. Fortunately, efficient and very enhanced cleavage of target RNAs compared with those with DNAs was observed for PRNA-DNA chimera/RNA complex by RNaseH. Regulation of protein synthesis by PRNA-DNA chimera was also evaluated by an in vitro cell-free protein synthesis system and in vivo, and effective regulation was observed.