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81.
Tadanobu Takahashi Sawako Kawagishi Midori Masuda Takashi Suzuki 《Glycoconjugate journal》2013,30(7):709-716
Association of a sulfated galactosyl ceramide, sulfatide, with the viral envelope glycoprotein hemagglutinin (HA) delivered to the cell surface is required for influenza A virus (IAV) replication through efficient translocation of the newly synthesized viral nucleoprotein from the nucleus to the cytoplasm. To determine whether the ectodomain of HA can bind to sulfatide, a secreted-type HA (sHA), in which the transmembrane region and cytoplasmic tail were deleted, was generated by using a baculovirus expression system. The receptor binding ability and antigenic structure of sHA were evaluated by a hemagglutination assay, solid-phase binding assay and hemagglutination inhibition assay. sHA showed subtype-specific antigenicity and binding ability to both sulfatide and gangliosides. Kinetics of sHA binding to sulfatide and GD1a was demonstrated by quartz crystal microbalance (QCM) analysis. QCM analysis showed that the sHA bound with the association rate constant (k on) of 1.41?×?104 M?1 sec?1, dissociation rate constant (k off) of 2.03?×?10?4 sec?1 and K d of 1.44?×?10?8 M to sulfatide immobilized on a sensor chip. The k off values of sHA were similar for sulfatide and GD1a, whereas the k on value of sHA binding to sulfatide was 2.56-times lower than that of sHA binding to GD1a. The results indicate that sulfatide directly binds to the ectodomain of HA with high affinity. 相似文献
82.
83.
Yuriko Furuya Atsushi Inagaki Masud Khan Kaoru Mori Josef M. Penninger Midori Nakamura Nobuyuki Udagawa Kazuhiro Aoki Keiichi Ohya Kohji Uchida Hisataka Yasuda 《The Journal of biological chemistry》2013,288(8):5562-5571
To date, parathyroid hormone is the only clinically available bone anabolic drug. The major difficulty in the development of such drugs is the lack of clarification of the mechanisms regulating osteoblast differentiation and bone formation. Here, we report a peptide (W9) known to abrogate osteoclast differentiation in vivo via blocking receptor activator of nuclear factor-κB ligand (RANKL)-RANK signaling that we surprisingly found exhibits a bone anabolic effect in vivo. Subcutaneous administration of W9 three times/day for 5 days significantly augmented bone mineral density in mouse cortical bone. Histomorphometric analysis showed a decrease in osteoclastogenesis in the distal femoral metaphysis and a significant increase in bone formation in the femoral diaphysis. Our findings suggest that W9 exerts bone anabolic activity. To clarify the mechanisms involved in this activity, we investigated the effects of W9 on osteoblast differentiation/mineralization in MC3T3-E1 (E1) cells. W9 markedly increased alkaline phosphatase (a marker enzyme of osteoblasts) activity and mineralization as shown by alizarin red staining. Gene expression of several osteogenesis-related factors was increased in W9-treated E1 cells. Addition of W9 activated p38 MAPK and Smad1/5/8 in E1 cells, and W9 showed osteogenesis stimulatory activity synergistically with BMP-2 in vitro and ectopic bone formation. Knockdown of RANKL expression in E1 cells reduced the effect of W9. Furthermore, W9 showed a weak effect on RANKL-deficient osteoblasts in alkaline phosphatase assay. Taken together, our findings suggest that this peptide may be useful for the treatment of bone diseases, and W9 achieves its bone anabolic activity through RANKL on osteoblasts accompanied by production of several autocrine factors. 相似文献
84.
Takanori Awata Mamoru Oshiki Tomonori Kindaichi Noriatsu Ozaki Akiyoshi Ohashi Satoshi Okabe 《Applied and environmental microbiology》2013,79(13):4145-4148
The phylogenetic affiliation and physiological characteristics (e.g., Ks and maximum specific growth rate [μmax]) of an anaerobic ammonium oxidation (anammox) bacterium, “Candidatus Scalindua sp.,” enriched from the marine sediment of Hiroshima Bay, Japan, were investigated. “Candidatus Scalindua sp.” exhibits higher affinity for nitrite and a lower growth rate and yield than the known anammox species. 相似文献
85.
Masakazu Atobe Kenji Naganuma Masashi Kawanishi Akifumi Morimoto Ken-ichi Kasahara Shigeki Ohashi Hiroko Suzuki Takahiko Hayashi Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(22):6064-6067
We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics. 相似文献
86.
Chie Hashimoto Tetsuo Narumi Hiroyuki Otsuki Yuki Hirota Hiroshi Arai Kazuhisa Yoshimura Shigeyoshi Harada Nami Ohashi Wataru Nomura Tomoyuki Miura Tatsuhiko Igarashi Shuzo Matsushita Hirokazu Tamamura 《Bioorganic & medicinal chemistry》2013,21(24):7884-7889
To date, several small molecules of CD4 mimics, which can suppress competitively the interaction between an HIV-1 envelope glycoprotein gp120 and a cellular surface protein CD4, have been reported as viral entry inhibitors. A lead compound 2 (YYA-021) with relatively high potency and low cytotoxicity has been identified previously by SAR studies. In the present study, the pharmacokinetics of the intravenous administration of compound 2 in rats and rhesus macaques is reported. The half-lives of compound 2 in blood in rats and rhesus macaques suggest that compound 2 shows wide tissue distribution and relatively high distribution volumes. A few hours after the injection, both plasma concentrations of compound 2 maintained micromolar levels, indicating it might have promise for intravenous administration when used combinatorially with anti-gp120 monoclonal antibodies. 相似文献
87.
Youichi Kawakita Masaki Seto Tomohiro Ohashi Toshiya Tamura Tadashi Yusa Hiroshi Miki Hidehisa Iwata Hidenori Kamiguchi Toshimasa Tanaka Satoshi Sogabe Yoshikazu Ohta Tomoyasu Ishikawa 《Bioorganic & medicinal chemistry》2013,21(8):2250-2261
A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit into the ATP binding site of the HER2/EGFR proteins. The synthesis of this scaffold was accomplished by an intramolecular Claisen-type condensation. As the results of optimization lead us to 4-anilino and 6-functional groups, we discovered 6-substituted amide derivative 19b, which has a 1-benzothiophen-4-yloxy group attached to the 4-anilino group. An X-ray co-crystal structure of 19b with EGFR demonstrated that the N-1 and N-3 nitrogens of the pyrimido[4,5-b]azepine scaffold make hydrogen-bonding interactions with the main chain NH of Met793 and the side chain of Thr854 via a water-mediated hydrogen bond network, respectively. In addition, the NH proton at the 9-position makes an additional hydrogen bond with the carbonyl group of Met793, as we expected. Compound 19b revealed potent HER2/EGFR kinase (IC50: 24/36 nM) and BT474 cell growth (GI50: 18 nM) inhibitory activities based on its pseudo-irreversible (PI) profile. 相似文献
88.
Masao Ohashi Takuji Oyama Endy Widya Putranto Tsuyoshi Waku Hiromi Nobusada Ken Kataoka Kenji Matsuno Masakazu Yashiro Kosuke Morikawa Nam-ho Huh Hiroyuki Miyachi 《Bioorganic & medicinal chemistry》2013,21(8):2319-2332
In the continuing study directed toward the development of peroxisome proliferator-activated receptor gamma (hPPARγ) agonist, we attempted to improve the water solubility of our previously developed hPPARγ-selective agonist 3, which is insufficiently soluble for practical use, by employing two strategies: introducing substituents to reduce its molecular planarity and decreasing its hydrophobicity via replacement of the adamantyl group with a heteroaromatic ring. The first approach proved ineffective, but the second was productive. Here, we report the design and synthesis of a series of α-benzyl phenylpropanoic acid-type hPPARγ partial agonists with improved aqueous solubility. Among them, we selected (R)-7j, which activates hPPARγ to the extent of about 65% of the maximum observed with a full agonist, for further evaluation. The ligand-binding mode and the reason for the partial-agonistic activity are discussed based on X-ray-determined structure of the complex of hPPARγ ligand-binding domain (LBD) and (R)-7j with previously reported ligand-LDB structures. Preliminal apoptotic effect of (R)-7j against human scirrhous gastric cancer cell line OCUM-2MD3 is also described. 相似文献
89.
Kazuo Tanaka Hiroshi Okada Wataru Ohashi Jong-Hwan Jeon Kenichi Inafuku Yoshiki Chujo 《Bioorganic & medicinal chemistry》2013,21(10):2678-2681
The influence on the efficiencies of the triplet–triplet annihilation (TTA)-supported upconversion by oxygen under biomimetic conditions was investigated. From the solution containing the dendrimer complexes based on polyhedral oligomeric silsesquioxane (POSS)-core dendrimer with the Pt complex of octaethylporphyrin (PtOEP) and anthracene in PBS, the fluorescence emission of anthracene depending on the dissolved oxygen (DO) concentrations via the TTA-supported upconversion was obtained with the excitation light at 540 nm. In particular, we observed strong emission only under hypoxic conditions. In addition, it was found that the emission intensity via TTA-supported upconversion can be reversibly regulated by the DO concentrations in the solution. 相似文献
90.
Yoshitami Ohashi Hiroshi Abe Yukio Ito 《Bioscience, biotechnology, and biochemistry》2013,77(10):2283-2287
From the acid hydrolyzate of the antibiotic YA–56 X (Zorbamycin) and Y belonging to the phleomycin-bleomycin group, 3 unique amino acids were isolated and their structures were determined to be β-hydroxy-L-valine and 2-(3′-amino-tetrahydrofuryl-2′-yl)-propionic acid and an isomer of the latter compound.Considerations of NMR of the antibiotic YA-56 and of the reaction conditions led us to a view that the latter two new amino acids were not an integral part of the YA–56 molecule but were artifacts derived from 4-amino-3,6-dihydroxy-2-methyhexanoic acid constituting of YA–56 X and Y. 相似文献