Izuru Ando
Japan Tobacco
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Publication
Featured researches published by Izuru Ando.
Antimicrobial Agents and Chemotherapy | 2012
Izuru Ando; Tsuyoshi Adachi; Naoki Ogura; Yukiyo Toyonaga; Kazuyuki Sugimoto; Hiroyuki Abe; Masafumi Kamada; Toru Noguchi
ABSTRACT JTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections.
Virology | 2008
Tohru Noguchi; Tomoko Otsubaki; Izuru Ando; Naoki Ogura; Satoru Ikeda; Kunitada Shimotohno
Hepatitis C virus (HCV) proteins appear to play an important role in IFN-resistance, but the molecular mechanism remains unclear. To clarify the mechanism in HCV replicon RNA harboring Huh-7 cells (Huh-9-13), we isolated cellular clones with impaired IFNalpha-sensitivity. Huh-9-13 was cultured for approximately 2 months in the presence of IFNalpha, and 4 IFNalpha-resistant cell clones showing significant resistances were obtained. When total RNA from clones was introduced into Huh-7 cells, the transfected cells also exhibited IFNalpha-resistance. Although no common mutations were present, mutations in NS3 and NS5A regions were accumulated. Transactivation of IFNalpha and IFNalpha-stimulated Stat-1 phosphorylation were reduced, and the elimination of HCV replicon RNA from the clones restored the IFNalpha signaling. These results suggest that the mutations in the HCV replicon RNA, at least in part, cause an inhibition of IFN signaling and are important for acquisition of IFNalpha resistance in Huh-9-13.
Intervirology | 2013
Izuru Ando; Naoki Ogura; Yukiyo Toyonaga; Kunihiro Hirahara; Tsutomu Shibata; Toru Noguchi
JTK-853 is a novel, non-nucleoside, palm site-binding hepatitis C virus (HCV) polymerase inhibitor that has demonstrated antiviral activity in HCV-infected patients during 3 days of treatment. To estimate the genetic barrier of JTK-853 to resistance in vitro, colony formation assays were conducted using HCV replicon cells (genotypes 1a and 1b). The colony formation assays revealed that the numbers of resistant colonies for JTK-853 were much lower than those for other direct-acting antivirals, including palm site- or thumb pocket-binding non-nucleoside HCV polymerase inhibitors (NNIs), an NS5A inhibitor (NS5Ai), and a protease inhibitor (PI). Furthermore, the numbers of resistant colonies for JTK-853 in combination with the NS5Ai or PI were lower than those for other combinations of NS5Ai + NNI, and NS5Ai + PI. Our findings demonstrate that JTK-853 has a high genetic barrier to resistance, and suggest that its combination therapies will be potent in suppressing the emergence of drug resistance in HCV-infected patients.
Antimicrobial Agents and Chemotherapy | 2013
Naoki Ogura; Yukiyo Toyonaga; Izuru Ando; Kunihiro Hirahara; Tsutomu Shibata; Gabriela Turcanu; Sudhakar Pai; Kan Yee; Barbara Gerhardt; Maribel Rodriguez-Torres; Toru Noguchi
ABSTRACT JTK-853, a palm site-binding NS5B nonnucleoside polymerase inhibitor, shows antiviral activity in vitro and in hepatitis C virus (HCV)-infected patients. Here, we report the results of genotypic and phenotypic analyses of resistant variants in 24 HCV genotype 1-infected patients who received JTK-853 (800, 1,200, or 1,600 mg twice daily or 1,200 mg three times daily) in a 3-day monotherapy. Viral resistance in NS5B was investigated using HCV RNA isolated from serum specimens from the patients. At the end of treatment (EOT) with JTK-853, the amino acid substitutions M414T (methionine [M] in position 414 at baseline was replaced with threonine [T] at EOT), C445R (cysteine [C] in position 445 at baseline was replaced with arginine [R] at EOT), Y448C/H (tyrosine [Y] in position 448 at baseline was replaced with cysteine [C] or histidine [H] at EOT), and L466F (leucine [L] in position 466 at baseline was replaced with phenylalanine [F] at EOT), which are known to be typical resistant variants of nonnucleoside polymerase inhibitors, were observed in a clonal sequencing analysis. These substitutions were also selected by a treatment with JTK-853 in vitro, and the 50% effective concentration of JTK-853 in the M414T-, C445F-, Y448H-, and L466V-harboring replicons attenuated the susceptibility by 44-, 5-, 6-, and 21-fold, respectively, compared with that in the wild-type replicon (Con1). These findings suggest that amino acid substitutions of M414T, C445R, Y448C/H, and L466F are thought to be viral resistance mutations in HCV-infected patients receiving JTK-853 in a 3-day monotherapy.
Journal of Medicinal Chemistry | 2006
Shintaro Hirashima; Takayoshi Suzuki; Tomio Ishida; Satoru Noji; Shinji Yata; Izuru Ando; Masakazu Komatsu; Satoru Ikeda; Hiromasa Hashimoto
Bioorganic & Medicinal Chemistry Letters | 2006
Tomio Ishida; Takayoshi Suzuki; Shintaro Hirashima; Kenji Mizutani; Atsuhito Yoshida; Izuru Ando; Satoru Ikeda; Tsuyoshi Adachi; Hiromasa Hashimoto
Journal of Medicinal Chemistry | 2006
Kazutaka Ikegashira; Takahiro Oka; Shintaro Hirashima; Satoru Noji; Hiroshi Yamanaka; Yoshinori Hara; Tsuyoshi Adachi; Junichiro Tsuruha; Satoki Doi; Yasunori Hase; Toru Noguchi; Izuru Ando; Naoki Ogura; Satoru Ikeda; Hiromasa Hashimoto
Archive | 2007
Takahiro Oka; Kazutaka Ikegashira; Shintaro Hirashima; Hiroshi Yamanaka; Satoru Noji; Yasushi Niwa; Yoko Matsumoto; Toshihiro Sato; Izuru Ando; Yukihiro Nomura
Archive | 2005
Takahiro Oka; Kazutaka Ikegashira; Shintaro Hirashima; Hiroshi Yamanaka; Satoru Noji; Yasushi Niwa; Yoko Matsumoto; Toshihiro Sato; Izuru Ando; Yukihiro Nomura
Bioorganic & Medicinal Chemistry Letters | 2007
Shintaro Hirashima; Takahiro Oka; Kazutaka Ikegashira; Satoru Noji; Hiroshi Yamanaka; Yoshinori Hara; Hiroyuki Goto; Ryo Mizojiri; Yasushi Niwa; Toru Noguchi; Izuru Ando; Satoru Ikeda; Hiromasa Hashimoto