Mechanism of resistance to translocation defective reverse transcriptase inhibitors

• Project/Area Number: 23590636
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Tohoku University
• Principal Investigator: ASHINO Yugo 東北大学, 医学(系)研究科(研究院), 准教授 (20361082)
• Co-Investigator(Kenkyū-buntansha): KODAMA Eiichi 東北大学, 大学院医学系研究科, 講師 (50271151)
• Project Period (FY): 2011-04-28 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: ウイルス / ＨＩＶ / 薬剤耐性 / 逆転写酵素 / 多剤耐性 / HIV

Research Abstract

A novel nucleoside reverse transcriptase (RT) inhibitor, 4'-ethynyl-2-fluoro-deoxyadenosine (EFdA) inhibits translocation activity of RT. To elucidate mechanism of the action in detail, resistant HIV-1 and -2 variants to EFdA were induced in vitro. M184I/V in the RT was identified as the primary mutation, while A158T and T165M/R were considered as the secondary mutations. M184I/V much reduced replication kinetics of HIV, but some of the secondary mutations improved the reduced replication. Data obtained from enzymatic assays with recombinant RT well supported those from viral assays. In this study, we provide crucial information of key amino aicds for tranlocation activity and of drug design for novel inhibitors.

Research Products

• [Journal Article] A man from South Asia presenting with abdominal pain (2014)
  • Author(s): Shiratori B, Usami O, Hattori T, Ashino Y.
  • Journal Title: BMJ Case Rep Volume: 7 Pages: bcr2013201716-bcr2013201716
  • DOI: 10.1136/bcr-2013-201716
  • Peer Reviewed
• [Journal Article] Acyclovir reduces the duration of fever in patients with infectious mononucleosis-like illness (2013)
  • Author(s): Usami O, Saitoh H, Ashino Y, Hattori T.
  • Journal Title: Tohoku J Exp Med Volume: 229(2) Pages: 137-142
  • NAID: 10031155455
  • Peer Reviewed
• [Journal Article] Development of Small Molecule HIV-1 Fusion Inhibitors: Linking Biology to Chemistry. (2013)
  • Author(s): Miyamoto F, Kodama EN
  • Journal Title: Curr Pharm Des. Volume: 19 Issue: 10 Pages: 1827-1834
  • DOI: 10.2174/1381612811319100007
  • Peer Reviewed
• [Journal Article] Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design. (2013)
  • Author(s): Izumi K, Kawaji K, Miyamoto F, Shimane K, Shimura K, Sakagami Y, Hattori T, Watanabe K, Oishi S, Fujii N, Matsuoka M, Kaku M, Sarafianos SG, Kodama EN.
  • Journal Title: Int J Biochem Cell Biol. Volume: 45 Issue: 4 Pages: 908-915
  • DOI: 10.1016/j.biocel.2013.01.015
  • Peer Reviewed
• [Journal Article] Acyclovir Reduces the Duration of Fever in Patients with Infectious Mononucleosis-like Illness (2013)
  • Author(s): Usami O, Saitoh H, Ashino Y, Hattori T.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 229 Issue: 2 Pages: 137-142
  • DOI: 10.1620/tjem.229.137
  • NAID: 10031155455
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Effect of translocation defective reverse transcriptase inhibitors on the activity of N348I, a connection subdomain drug resistant HIV-1 reverse transcriptase mutant. (2012)
  • Author(s): Michailidis E, Singh K, Ryan EM, Hachiya A, Ong YT, Kirby KA, Marchand B, Kodama EN, Mitsuya H, Parniak MA, Sarafianos SG.
  • Journal Title: Cell Mol Biol (Noisy-le-grand). Volume: 58 Pages: 187-195
  • DOI: 10.1155/2012/586401
  • Peer Reviewed
• [Journal Article] Elevated anti-tuberculous glycolipid antibody titres in healthy adults and tuberculosis patients in Thailand. (2012)
  • Author(s): Siddiqi UR, Punpunich W, Chuchottaworn C, Jindakul S, Ashino Y, Saitoh H, Okada M, Chotpittayasunondh T, Hattori T
  • Journal Title: Int J Tuberc Lung Dis. Volume: 4 Issue: 4 Pages: 532-538
  • DOI: 10.5588/ijtld.10.0764
  • Peer Reviewed
• [Journal Article] HIV-1 reverse transcriptase (RT) polymorphism 172K suppresses the effect of clinically relevant drug resistance mutations to both nucleoside and non-nucleoside RT inhibitors. (2012)
  • Author(s): Hachiya A, Marchand B, Kirby KA, Michailidis E, Tu X, Palczewski K, Ong YT, Li Z, Griffin DT, Schuckmann MM, Tanuma J, Oka S, Singh K, Kodama EN, Sarafianos SG.
  • Journal Title: J Biol Chem. Volume: 287 Issue: 35 Pages: 29988-29999
  • DOI: 10.1074/jbc.m112.351551
  • Peer Reviewed
• [Journal Article] Biochemical, inhibition, and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase. (2012)
  • Author(s): Tanyaradzwa P. Ei-Ichi Kodama, et al.
  • Journal Title: Nucleic Acids Research Volume: 40 Issue: 1 Pages: 345-359
  • DOI: 10.1093/nar/gkr694
  • Peer Reviewed
• [Journal Article] Development and application of fluorescent SDF-1 derivatives (2012)
  • Author(s): Masuda R, Oishi S, Tanahara N, Ohno H, Hirasawa A, Tsujimoto G, Kodama E, Matsuoka M, Fujii N.
  • Journal Title: Future Med. Chem. Volume: 4 Issue: 7 Pages: 837-844
  • DOI: 10.4155/fmc.12.31
  • NAID: 120005285488
  • Peer Reviewed
• [Journal Article] Rapid Decrease of Plasma Galectin-9 Levels in Patients with Acute HIV Infection after Therapy (2012)
  • Author(s): Saitoh H, Ashino Y, Chagan-Yasutan H, Niki T, Hirashima M, Hattori T.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 228 Issue: 2 Pages: 157-161
  • DOI: 10.1620/tjem.228.157
  • NAID: 130004460015
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Distinct Clinical Features in Nontuberculous Mycobacterial Disease with or without Latent Tuberculosis Infection (2012)
  • Author(s): Siddiqi UR, Chagan-Yasutan H, Nakajima C, Saitoh H, Ashino Y, Usami O, Shiratori B, Usuzawa M, Suzuki Y, Hattori T.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 226 Issue: 4 Pages: 313-319
  • DOI: 10.1620/tjem.226.313
  • NAID: 130004459977
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Potent anti-HIV-1 activity of N-HR-derived peptides including a deep pocket-forming region without antagonistic effects (2011)
  • Author(s): Watanabe K, Oishi S, Fujii on T-20.Izumi K, N, Matsuoka M, Sarafianos SG, Kodama EN
  • Journal Title: Antivir Chem Volume: 22 Issue: 1 Pages: 51-55
  • DOI: 10.3851/imp1836
• [Journal Article] K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism (2011)
  • Author(s): Hachiya A, Kodama EN, Schuckmann MM, Kirby KA, Michailidis E, Sakagami Y, Oka S, Singh K, Sarafianos SG
  • Journal Title: PLoS One Volume: 6(1)
  • Peer Reviewed
• [Journal Article] The sugar ring conformation of 4'-ethynyl-2-fluoro-2'-deoxyadenosine and its recognition by the polymerase active site of HIV reverse transcriptase (2011)
  • Author(s): Kirby KA, Singh K, Michailidis E, Marchand B, Kodama EN, Ashida N, Mitsuya H, Parniak MA, Sarafianos SG
  • Journal Title: Cell Mol Biol (Noisy-le-grand) Volume: 57(1) Pages: 40-6
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119259/
  • Peer Reviewed
• [Presentation] Sustained Activity of 4'-Ethynyl Nucleosides to Variants with M184V Mutation in HIV-1 Reverse Transcriptase (2012)
  • Author(s): Fusako Miyamoto,Kumi Kawaji,Toshio Hattori, Hiroaki Mitsuya, Stefan G Sarafianos is, Eiichi N Kodama
  • Organizer: 25th In- ternational Conference on Antiviral Research
  • Place of Presentation: Sapporo, Japan
• [Presentation] Effect of 4'- and 2-NRTI Substitu- tions on the Inhibition Mechanism of HIV Re- verse Transcriptase and Toxicity (2012)
  • Author(s): Eleftherios Michailidis, Jordan Wilkins, Emily M. Ryan, Atsuko Hachiya, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos
  • Organizer: 25th In- ternational Conference on Antiviral Research
  • Place of Presentation: Sapporo, Japan
• [Presentation] The Combination of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine with Rilpivirine Shows Synergistic Anti-HIV-1 Activ- ity In Vitro (2012)
  • Author(s): Atsuko Hachiya, Bruno Marchand, Eleftherios Michailidis, Eiichi N Kodama, Michael A Parni- ak, Hiroaki Mitsuya, Shinichi Oka, Stefan G Sarafianos
  • Organizer: 25th In- ternational Conference on Antiviral Research
  • Place of Presentation: Sapporo, Japan
• [Presentation] MINICICLIN投与によるヒト免疫不全ウイルス(HIV)持続感染への効果 (2012)
  • Author(s): 芦野有悟、宇佐美修、齊藤弘樹、服部俊夫、賀来満夫
  • Organizer: 第26回日本エイズ学会学術集会
  • Place of Presentation: 神奈川、日本
• [Presentation] A novel peptide derived from measles virus fusion protein inhibits the replication of subacute sclerosing panencephalitis (SSPE) virus in vitro and in vivo. (2012)
  • Author(s): Masahiro Watanabe, Koichi Hashimoto, Yusaku Abe, Eiichi Kodama, Ryota Nabika, Shinya Oishi, Nobutaka Fujii, Mitsuaki Hosoya
  • Organizer: 25th International Conference on Antiviral Research.
  • Place of Presentation: 札幌
• [Presentation] The Combination of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine with Rilpivirine Shows Synergistic Anti-HIV-1 Activity In Vitro. (2012)
  • Author(s): Atsuko Hachiya, Bruno Marchand, Eleftherios Michailidis, Eiichi N Kodama, Michael A Parniak, Hiroaki Mitsuya, Shinichi Oka, Stefan G Sarafianos.
  • Organizer: 25th International Conference on Antiviral Research.
  • Place of Presentation: 札幌
• [Presentation] Effect of 4'- and 2-NRTI Substitutions on the Inhibition Mechanism of HIV Reverse Transcriptase and Toxicity. (2012)
  • Author(s): Eleftherios Michailidis, Jordan Wilkins, Emily M. Ryan, Atsuko Hachiya, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Stefan G. Sarafianos.
  • Organizer: 25th International Conference on Antiviral Research.
  • Place of Presentation: 札幌
• [Presentation] Sustained Activity of 4'-Ethynyl Nucleosides to Variants with M184V Mutation in HIV-1 Reverse Transcriptase. (2012)
  • Author(s): Fusako Miyamoto, Kumi Kawaji, Toshio Hattori, Hiroaki Mitsuya, Stefan G. Sarafianos, Eiichi N. Kodama.
  • Organizer: 25th International Conference on Antiviral Research.
  • Place of Presentation: 札幌
• [Presentation] 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a translocation defective reverse transcriptase inhibitor with highly potent activity against diverse multi-drug-resistant HIV-1 variants. (2012)
  • Author(s): Hiroaki Mitsuya, Eiichi Kodama, Hirotomo Nakata, Shinichro Hattori, Seiji Okada, Kenji Maeda, Michael A. Parniak, and Stefan G. Sarafianos.
  • Organizer: 13th Kmamoto AIDS Seminar-GCOE Joint International Symposium
  • Place of Presentation: 熊本
• [Presentation] Combinations of 4'-ethynyl-2-fluoro-2'-deoxyadenosine with rilpivirine show synergistic anti-HIV activity in vitro. (2012)
  • Author(s): Atsuko Hachiya, Eiichi N. Kodama et al.
  • Organizer: 13th Kmamoto AIDS Seminar-GCOE Joint International Symposium
  • Place of Presentation: 熊本
• [Presentation] MINICICLIN投与によるヒト免疫不全ウイルス(HIV)持続感染への効果 (2012)
  • Author(s): 芦野有悟、宇佐美修、齊藤弘樹、服部俊夫、賀来満夫
  • Organizer: 第26回日本エイズ学会学術集会
  • Place of Presentation: 神奈川
• [Presentation] Administration of Acyclovir for Acute Lymphadenopathy Reduces Duration of Hospitalization and Febrile Period (2012)
  • Author(s): Yugo Ashino, Osamu Usami, Hiroki, Saitoh, and Toshio Hattori
  • Organizer: 第9回日中ウイルス学会
  • Place of Presentation: 札幌