Kikuchi, Haruhisa



Faculty of Pharmacy, Department of Pharmacy (Shiba-Kyoritsu)




Papers 【 Display / hide

  • Inhibition of Plasmodium falciparum Lysyl-tRNA Synthetase via a Piperidine-Ring Scaffold Inspired Cladosporin Analogues

    Babbar P., Sato M., Manickam Y., Mishra S., Harlos K., Gupta S., Parvez S., Kikuchi H., Sharma A.

    ChemBioChem (ChemBioChem)  22 ( 14 ) 2468 - 2477 2021.07

    ISSN  14394227

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    Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) represents a promising therapeutic anti-malarial target. Cladosporin was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X-ray crystallography reveal compounds that are moderate in potency. Co-crystals of Cla−B and Cla−C with PfKRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.

  • Dictyostelium differentiation-inducing factor-1 promotes glucose uptake, at least in part, via an ampk-dependent pathway in mouse 3t3-l1 cells

    Kubohara Y., Homma Y., Shibata H., Oshima Y., Kikuchi H.

    International Journal of Molecular Sciences (International Journal of Molecular Sciences)  22 ( 5 ) 1 - 13 2021.03

    ISSN  16616596

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    Differentiation-inducing factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2–20 μM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10–20 μM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.

  • Effect of mushroom polysaccharides from Pleurotus eryngii on obesity and gut microbiota in mice fed a high-fat diet

    Nakahara D., Nan C., Mori K., Hanayama M., Kikuchi H., Hirai S., Egashira Y.

    European Journal of Nutrition (European Journal of Nutrition)  59 ( 7 ) 3231 - 3244 2020.10

    ISSN  14366207

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    Purpose: Mushrooms are reported to have a variety of health-promoting activities. However, little information is available on the effects of intake of polysaccharides from Pleurotus eryngii on obesity. In this study, we investigated the effects of P. eryngii polysaccharides on obesity and gut microbiota in mice fed a high-fat diet. Methods: Soluble polysaccharides were extracted from P. eryngii using hot water. C57BL/6J mice were fed a standard diet (ST), a high-fat diet (HF), or HF with 1% or 5% P. eryngii polysaccharide fraction (LP or HP) for 16 weeks. Adipose tissues were weighed and blood parameters were measured. Expression of genes involved in fatty acid and cholesterol metabolism was assessed by real-time quantitative PCR. The gut microbiota composition was analysed by 16S rRNA gene sequencing. Results: Body weight gain and mesenteric fat tissue were lower in the HP group than in the HF group. In the HP group, serum total cholesterol and LDL cholesterol levels decreased, and lipid and total bile acids in faeces increased. Mice in the HP group showed increased expression of the LDLR gene in the liver and GPR43 in fat. The relative abundance of Firmicutes was significantly higher in the HF and HP groups than in the ST group. The abundance of some short-chain fatty acid-producing gut bacteria was altered by P. eryngii polysaccharides. Conclusions: These results provide the first evidence that P. eryngii polysaccharides have anti-obesity and LDL cholesterol-lowering effects in obese mice through increased excretion of bile acids and lipids and altered microbiota.

  • Two new terpenes isolated from dictyostelium cellular slime molds

    Sasaki H., Kubohara Y., Ishigaki H., Takahashi K., Eguchi H., Sugawara A., Oshima Y., Kikuchi H.

    Molecules (Molecules)  25 ( 12 )  2020.06

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    We report a protoilludane-type sesquiterpene, mucoroidiol, and a geranylated bicyclogermacranol, firmibasiol, isolated from Dictyostelium cellular slime molds. The methanol extracts of the fruiting bodies of cellular slime molds were separated by chromatographic methods to give these compounds. Their structures have been established by several spectral means. Mucoroidiol and firmibasiol are the first examples of more modified and oxidized terpenoids isolated from cellular slime molds. Mucoroidiol showed moderate osteoclast-differentiation inhibitory activity despite demonstrating very weak cell-proliferation inhibitory activity. Therefore, cellular slime molds produce considerably diverse secondary metabolites, and they are promising sources of new natural product chemistry.

  • An automated microliter-scale high-throughput screening system (MSHTS) for real-time monitoring of protein aggregation using quantum-dot nanoprobes

    Sasaki R., Tainaka R., Ando Y., Hashi Y., Deepak H.V., Suga Y., Murai Y., Anetai M., Monde K., Ohta K., Ito I., Kikuchi H., Oshima Y., Endo Y., Nakao H., Sakono M., Uwai K., Tokuraku K.

    Scientific Reports (Scientific Reports)  9 ( 1 )  2019.12

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    Protein aggregation is the principal component of numerous protein misfolding pathologies termed proteinopathies, such as Alzheimer’s disease, Parkinson’s disease, prion disease, and AA amyloidosis with unmet treatment needs. Protein aggregation inhibitors have great potential for the prevention and treatment of proteinopathies. Here we report the development of an automated real-time microliter-scale high throughput screening (MSHTS) system for amyloid aggregation inhibitors using quantum-dot nanoprobes. Screening 504 crude extracts and 134 low molecular weight aromatic compounds revealed the relationship of amyloid-β (Aβ) aggregation inhibitory activities of plant extracts using a plant-based classification. Within the eudicots, rosids, Geraniales and Myrtales showed higher activity. Screening low molecular weight aromatic compounds demonstrated that the structure of tropolone endows it with potential Aβ aggregation inhibitory activity. The activity of the most active tropolone derivative was higher than that of rosmarinic acid. MSHTS also identified three chaperone molecules as tau aggregation inhibitors. These results demonstrate that our automated MSHTS system is a novel and robust tool that can be adapted to a wide range of compounds and aggregation-prone polypeptides.

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Reviews, Commentaries, etc. 【 Display / hide

  • Erratum: Removal of the E-Olefin Barrier of Humulene Leading to Unnatural Terpenoid-like Skeletons (Organic Letters (2018) 20, 22, (7313-7320) DOI: 10.1021/acs.orglett.8b03259)

    Nishimura T., Kawai J., Oshima Y., Kikuchi H.

    Organic Letters (Organic Letters)  21 ( 4 )  2019.02

    ISSN  15237060

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    The structures of compounds 11 and 12 shown in Figure 2A were corrected by changing the relative configurations, although the structures in the Supporting Information were correct. Figure 2A is corrected as follows: The absolute configurations of compounds 15-19 drawn in Figure 3A and in the Supporting Information were corrected. Although the relative configurations shown in the Supporting Information were correct, the wrong assignment is because of drawing the absolute configuration at the C-6 position of 15- 17 in reverse. The corrected Figure 3A is as follows and and the revised Supporting Information with the corrected structures for compounds 15-17 is included with this Correction.

Research Projects of Competitive Funds, etc. 【 Display / hide

  • 天然化合物を越える多様性を有した生物活性指向型化合物ライブラリーの構築


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 菊地 晴久, Grant-in-Aid for Scientific Research (B), Principal Investigator


Courses Taught 【 Display / hide











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