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RESEARCH

Research Area : Applied Natural Product Chemistry

  • Prof.
    KIYOTA Hiromasa

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Investigation of inhibition mechanism of sialidase of influenza virus and development of novel inhibitors: difluorosialic acid and sulfo-sialic acid

Development of improved influenza sialidase inhibitors is critical to prepare for potential influenza pandemics. Based on the hypothesis that Tyr406 forms an acetal intermediate in the catalytic cycle of sialidase, we synthesized 2a,3a-difluorosialic acid (1) as a suitable probe to test if a covalent intermediate can be captured. As expected, X-ray crystallographic analysis revealed that 1 forms a covalent complex with Tyr406 of influenza silalidase. This indicated that Tyr406 attacks from the b-face of the substrate, leading to hydrolysis with retention (inversion and inversion) of the configuration. In addition, 1 possessed potent anti-influenza activity (including that of Tamiflu resistant virus) with IC50 inhibitory constants of 10 to 1000 nm, providing the first proof-of-concept for mechanism-based influenza sialidase inhibition.
In addition, a next-generation inhibitor, sulfo-sialic acid (2), was developed. The sialidase inhibitory activity of 2 was more potent than the corresponding carboxy and phosphono derivatives, presumably due to stronger attraction to the triarginyl binding site of the enzyme.

Research Area : Applied Natural Product Chemistry

  • Assoc. Prof.
    IZUMI Minoru

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Solid-Supported Combinatorial and Parallel Synthesis of Bioactive Compound Libraries.

The solid-phase strategy is a strong tool for high throughput synthesis and combinatorial chemistry. Synthetic intermediates are retained on the support and can be, therefore, quickly separated from the reaction mixture without extraction, concentration, and purification steps. Solid-phase synthesis is thus particularly advantageous for multi-step iterative synthesis. Various solid-phase automated synthesizers have been developed and are now commercially available. Our research focus on automated synthesis of bioactive compound and building- up of compound libraries by automatic synthesizer Nautilus 2400.

Chemo-Enzymatic Synthesis of glycosides and glycoconjugate.

Galactofuranose is a component of polysaccharides and glycoconjugates. There are few reports about the involvement of galactofuranosyltransferases and galactofuranosidases in the synthesis and degradation of galactofuranose-containing glycans. The cell walls of filamentous fungi in the genus Aspergillus include galactofuranose-containing polysaccharides and glycoconjugates, such as O-glycans, N-glycans, and fungal-type galactomannan, which are important for cell wall integrity. Our research interests focus on many problems that lie at the integrity of cell wall, we are especially investigating the methodology to synthesize glycosides and glycoconjugates by chemo-enzymatic methods including use of some enzyme.