Research
Faculty Members
Bioorganic Chemistry（Chemistry）
Yamaguchi TakaoAssociate professor
I received my PhD in 2008 from the Graduate School of Pharmaceutical Sciences, Osaka University, and I moved to University of Notre Dame and got started the research on inhibitors of bacterial cell-wall recycling. In 2010, I started chemical biology research focused on the mechanism of a novel type of cell-death inhibitor at RIKEN. Then, I came back to Osaka University in 2013 and have developed novel artificial nucleic acid for use in therapeutic oligonucleotides. I moved to The University of Tokyo as an Assistant Professor in 2014 and have developed several bioactive small molecules and target protein identification methods. From 2017, I have been an Associate Professor at Osaka University.
Research theme
Development of artificial nucleic acids for therapeutic oligonucleotides
Therapeutic oligonucleotides are novel modality that can target DNA and RNA, and have been attracting attention in recent years. We conduct a series of drug discovery (design, synthesis, and biophysical and biological evaluations) based on the development of novel artificial nucleic acids.
Labeling and chemical modification of proteins
Target identification is important step for understanding the mechanism of bioactive small molecules. We have been developing affinity labeling methods that can be used for a specific labeling of the target protein of bioactive small molecules even in living cells. We also develop chemical modification methods for peptides and proteins.
Development of analytical methods for oligonucleotide and mRNA therapeutics
As the approval of oligonucleotide therapeutics and mRNA-based medicines continues to accelerate, the development of analytical methods to ensure their quality has become increasingly important. We are developing methodologies, including LC/MS-based approaches, to achieve appropriate separation and analysis of target molecules and their associated impurities.
Representative achievements
Development of synthetic routes to 2′-O,4′-C-spirocyclopentylene-bridged nucleic acids: thymidine, guanosine, and adenosine. Chem. Eur. J. 2025, 31, e02995.
Cycloalkane incorporation into the 2′,4′-bridge of locked nucleic acid: enhancing nuclease stability, reducing phosphorothioate modifications, and lowering hepatotoxicity in antisense oligonucleotides. JACS Au 2025, 5, 5111–5120.
Phthalimide: a potential warhead for switchable and bioorthogonal conjugation. Chem. Commun. 2025, 61, 13417–13420.
Separation of deaminated impurities from the desired oligonucleotides using supercritical fluid chromatography. J. Chromatogr. A 2025, 1744, 465731.
Separation of the diastereomers of phosphorothioated siRNAs by anion-exchange chromatography under non-denaturing conditions. J. Chromatogr. A 2024, 1721, 464847.
Mechanism of the extremely high duplex-forming ability of oligonucleotides modified with N-tert-butylguanidine- or N-tert-butyl-N′-methylguanidine-bridged nucleic acids. Nucleic Acids Res. 2023, 51, 7749–7761.
Development of 8–17 XNAzymes that are functional in cells. Chem. Sci. 2023, 14, 7620–7629.
Specific fluorescence labeling of target proteins by using a ligand–4-azidophthalimide conjugate. Chem. Commun. 2017, 53, 8751–8754.
Synthesis and properties of 2′-O,4′-C-spirocyclopropylene bridged nucleic acid (scpBNA), an analogue of 2′,4′-BNA/LNA bearing a cyclopropane ring. Chem. Commun. 2015, 51, 9737–9740.
Turn-ON fluorescent affinity labeling using a small bifunctional O-nitrobenzoxadiazole unit. Chem. Sci. 2014, 5, 1021–1029.
