Establishment of virtual assay system by molecular dynamic simulation of HCV antiviral resistance

• Project/Area Number: 26670375
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: Sakamoto Naoya 北海道大学, 医学(系)研究科(研究院), 教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): ENDO TOSHINORI 北海道大学, 情報科学研究科, 教授 (00323692) ; SUDA GOKI 北海道大学, 医学研究科, 特任助教 (20447460)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ウイルス学 / 肝炎ウイルス / 分子動力学シミュレーション / C型肝炎 / 抗ウイルス療法 / 薬剤耐性変異

Outline of Final Research Achievements

1. We conducted a molecular dynamic simulation of NS5A protein, its dimer and NS5A inhibitor (daclatasvir), and designated individual optimal 3D structures.
2. We conducted a molecular dynamic simulations of NS5A dimer and daclatasvir on the ER membrane.
3. We conducted an in-vitro assay by using HCV replicon system and confirmed expected effects of resistance-associated substitutions.

Research Products

• [Journal Article] Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection (2016)
  • Author(s): Ito J, Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kumagai K, Kikuchi H, Miyagishima T, Kobayashi T, Kimura M, Yamasaki K, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Terashita K, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto
  • Journal Title: Hepatol Res Volume: in press Issue: 13 Pages: 1294-1303
  • DOI: 10.1111/hepr.12685
  • Peer Reviewed / Open Access
• [Journal Article] Viral life cycle of hepatitis B virus : host factors and druggable targets. (2016)
  • Author(s): Morikawa K, Suda G, Sakamoto N
  • Journal Title: Hepatol Res Volume: EPub Issue: 9 Pages: 871-877
  • DOI: 10.1111/hepr.12650
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C. (2016)
  • Author(s): Suda G, Kudo M, Nagasaka A, Furuya K, Yamamoto Y, Kobayashi T, Shinada K, Tateyama M, Konno J, Tsukuda Y, Yamasaki K, Kimura M, Umemura M, Izumi T, Tsunematsu S, Sato F, Terashita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N
  • Journal Title: J Gastroenterol Hepatol Volume: EPub Issue: 7 Pages: 733-740
  • DOI: 10.1007/s00535-016-1162-8
  • NAID: 120006313426
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma (2016)
  • Author(s): Terashita K, Chuma M, Hatanaka Y, Hatanaka K, Mitsuhashi T, Yokoo H, Ohmura T, Ishizu H, Muraoka S, Nagasaka A, Tsuji T, Yamamoto Y, Kurauchi N, Shimoyama N, Toyoda H, Kumada T, Kaneoka Y, Maeda A, Ogawa K, Natsuizaka M, Kamachi H, Kakisaka T, Kamiyama T, Taketomi A, Matsuno Y, Sakamoto N
  • Journal Title: J Clin Pathol Volume: in press Issue: 7 Pages: 593-599
  • DOI: 10.1136/jclinpath-2015-203115
  • Peer Reviewed
• [Journal Article] Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals. (2015)
  • Author(s): N. Nishida, J. Ohashi, M. Sugiyama, T. Tsuchiura, K. Yamamoto, K. Hino, M. Honda, S. Kaneko, H. Yatsuhashi, K. Koike, O. Yokosuka, E. Tanaka, A. Taketomi, M. Kurosaki, N. Izumi, N. Sakamoto, Y. Eguchi, T. Sasazuki, K. Tokunaga, and M. Mizokami
  • Journal Title: Tissue Antigens Volume: 5 Issue: 6 Pages: 406-412
  • DOI: 10.1111/tan.12684
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Amino acid polymorphisms in hepatitis C virus core affect infectious virus production and major histocompatibility complex class I molecule expression (2015)
  • Author(s): Tasaka-Fujita M, Sugiyama N, Kang W, Masaki T, Murayama A, Yamada N, Sugiyama R, Tsukuda S, Watashi K, Asahina Y, Sakamoto N, Wakita T, Shin EC, Kato T
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 13994-14002
  • DOI: 10.1038/srep13994
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions. (2015)
  • Author(s): Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kudo M, Chuganji Y, Tsukuda Y, Tsunematsu S, Sato F, Terasita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Fujita Y, Abe R, Taniguchi M, Nakagawa M, Asahina Y, Sakamoto N
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 8 Pages: 837-45
  • DOI: 10.1111/hepr.12421
  • NAID: 120005820706
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions. (2015)
  • Author(s): Chuma M, Terashita K, Sakamoto N
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 10
  • DOI: 10.1111/hepr.12459
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. (2015)
  • Author(s): Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
  • Journal Title: Hum Genet Volume: 134 Issue: 3 Pages: 279-289
  • DOI: 10.1007/s00439-014-1520-7
  • Peer Reviewed / Open Access
• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 6 Pages: 1075-84
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Open Access
• [Journal Article] Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. (2015)
  • Author(s): Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, Nakane K, Enomoto H, Ikeda F, Yanase M, Toyoda H, Genda T, Umemura T, Yatsuhashi H, Ide T et al.
  • Journal Title: Lancet Infect Dis Volume: 印刷中 Issue: 6 Pages: 645-653
  • DOI: 10.1016/s1473-3099(15)70099-x
  • Peer Reviewed / Open Access
• [Journal Article] ITPA genetic variants influence efficacy of PEG-IFN/RBV therapy in older patients infected with HCV genotype 1 and favourable IL28B type. (2014)
  • Author(s): Matsuura K, Tanaka Y, Watanabe T, Fujiwara K, Orito E, Kurosaki M, Izumi N, Sakamoto N, Enomoto N, Yatsuhashi H, Kusakabe A, Shinkai N, Nojiri S, Joh T, Mizokami M.
  • Journal Title: J Viral Hepat. Volume: 21 Issue: 7 Pages: 466-474
  • DOI: 10.1111/jvh.12171
  • Peer Reviewed
• [Journal Article] The J6JFH1 Strain of Hepatitis C Virus Infects Human B-Cells with Low Replication Efficacy. (2014)
  • Author(s): Nakai M, Seya T, Matsumoto M, Shimotohno K, Sakamoto N, Aly HH.
  • Journal Title: Viral Immunol. Volume: 27 Issue: 6 Pages: 285-294
  • DOI: 10.1089/vim.2013.0140
  • Peer Reviewed / Open Access
• [Journal Article] Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial. (2014)
  • Author(s): Omata M, Nishiguchi S, Ueno Y, Mochizuki H, Izumi N, Ikeda F, Toyoda H, Yokosuka O, Nirei K, Genda T, Umemura T, Takehara T, Sakamoto N, Nishigaki Y, Nakane K, Toda N, Ide T, Yanase M, Hino K et al.
  • Journal Title: J Viral Hepat Volume: 21 Issue: 11 Pages: 762-768
  • DOI: 10.1111/jvh.12312
  • Peer Reviewed