Application of molecular dynamics simulation to construct of virtual assay system of antiviral drug resistance

• Project/Area Number: 16K15420
• 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, 医学研究院, 教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): 須田 剛生 北海道大学, 大学病院, 特任助教 (20447460) ; 森川 賢一 北海道大学, 大学病院, 助教 (60384377)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ウイルス肝炎 / C型肝炎 / 薬剤耐性 / DAA薬剤耐性 / 医学

Outline of Final Research Achievements

We conducted molecular dynamics simulation assay to construct docking models of direct acting antivirals and the target viral protein and studied effects of resistance-associated mutations of the viral protein on the drug-protein binding affinity and the drug resistance. We further conducted in-vitro HCV replicon cell culture system and confirmed significant association of the calculated binding affinity and the phenotypic drug resistance. We confirmed that NS5A-P32del resistance mutation acquires strong resistance to all clinically available NS5A inhibitors in vitro.

Research Products

• [Journal Article] Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction (2018)
  • Author(s): Sho T, Suda G,, Nagasaka A, Yamamoto Y, Furuya K, Kumagai K, Uebayashi M, Terashita K, Kobayashi T, Tsunematsu I, Onodera M, Meguro T, Kimura M, Ito J, Umemura M, Izumi T, Kawagishi N, Ohara M, Ono Y, Nakai M, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N
  • Journal Title: Heptology Research Volume: in press Issue: 7 Pages: 529-538
  • DOI: 10.1111/hepr.13056
  • Peer Reviewed
• [Journal Article] Hepatitis C virus-induced innate immune responses in human iPS cell-derived hepatocyte-like cells (2017)
  • Author(s): Sakurai Fuminori、Kunito Takemaru、Takayama Kazuo、Hashimoto Rina、Tachibana Masashi、Sakamoto Naoya、Wakita Takaji、Mizuguchi Hiroyuki
  • Journal Title: Virus Research Volume: 242 Pages: 7-15
  • DOI: 10.1016/j.virusres.2017.09.004
  • Peer Reviewed
• [Journal Article] Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study (2017)
  • Author(s): Suda Goki、Morikawa Kenichi、et al.
  • Journal Title: Hepatol Res. Volume: 48 Issue: 3
  • DOI: 10.1111/hepr.12938
  • Peer Reviewed
• [Journal Article] Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C (2017)
  • Author(s): Kawagishi N.、Suda G.、Onozawa M.、Kimura M.、Maehara O.、Ohara M.、Izumi T.、Umemura M.、Ito J.、Nakai M.、Sho T.、Natsuizaka M.、Morikawa K.、Ogawa K.、Sakamoto N.
  • Journal Title: J Viral Hepat. Volume: 24 Issue: 12 Pages: 1098-1106
  • DOI: 10.1111/jvh.12737
  • Peer Reviewed
• [Journal Article] Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan (2017)
  • Author(s): Suda Goki、Morikawa Kenichi、et al.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 1 Pages: 119-128
  • DOI: 10.1007/s00535-017-1353-y
  • Peer Reviewed
• [Journal Article] Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy (2017)
  • Author(s): Suda G, Ogawa K, Yamamoto Y, Katagiri M, Furuya K, Kumagai K, Konno J, Kimura M, Kawagishi N, Ohara M, Umemura M, Ito J, Izumi T, Nakai M, Sho T, Natsuizaka M, Morikawa K, Tsubota A, Shimada N, Iio E, Tanaka Y, Sakamoto N; NORTE Study Group.
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 10 Pages: 1122-1129
  • DOI: 10.1007/s00535-017-1328-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Paradoxical Effects of Different Hepatitis C Viral Loads on Host DNA Damage and Repair Abilities. (2017)
  • Author(s): Wang SC, Lai KR, Li CY, Chiang CS, Yu GY, Sakamoto N, Tu WY, Hsieh MH, Huang JF, Chuang WL, Dai CY, Yu ML
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: 1-1
  • DOI: 10.1371/journal.pone.0164281
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus infected patients with renal impairment (2017)
  • Author(s): Suda G, Nagasaka A, Yamamoto Y, Furuya K, Kumagai K, Kudo M, Terashita K, Kobayashi T, Tsunematsu I, Yoshida J, Meguro T, Kimura M, Ito J, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N; NORTE Study Group.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1127-1136
  • DOI: 10.1111/hepr.12851
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Retinoid derivative Tp80 exhibits anti-hepatitis C virus activity through restoration of GI-GPx expression. (2017)
  • Author(s): Ngoc NB, Okuno Y, Ajiro M, Iida K, Denawa M, Yamamoto M, Sakamoto N, Kagechika H, Hagiwara M
  • Journal Title: J Med Virol Volume: Epub ahead of print Issue: 7 Pages: 1224-1234
  • DOI: 10.1002/jmv.24739
  • Peer Reviewed
• [Journal Article] Hepatitis B virus X protein impairs α-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protein phosphatase 2A. (2017)
  • Author(s): Tsunematsu S, Suda G, Yamasaki K, Kimura M, Izumi T, Umemura M, Ito J, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Tanaka Y, Watashi K, Wakita T, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 2 Pages: 267-275
  • DOI: 10.1002/jmv.24643
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection. (2016)
  • Author(s): Tsukuda Y, Suda G, Tsunematsu S, Ito J, Sato F, Terashita K, Nakai M, Sho T, Maehara O, Shimazaki T, Kimura M, Morikawa K, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Sakamoto N
  • Journal Title: J Med Virol Volume: 89 Issue: 5 Pages: 857-866
  • DOI: 10.1002/jmv.24692
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] Resistance Analyses of Japanese Hepatitis C-Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies. (2016)
  • Author(s): Mizokami M, Dvory-Sobol H, Izumi N, Nishiguchi S, Doehle B, Svarovskaia ES, De-Oertel S, Knox S, Brainard DM, Miller MD, Mo H, Sakamoto N, Takehara T, Omata M
  • Journal Title: J Viral Hepat Volume: 23 Issue: 10 Pages: 780-788
  • DOI: 10.1111/jvh.12549
  • Peer Reviewed