Development of antiviral agents targeting ATP-mediated excision

• Project/Area Number: 25670255
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Tohoku University
• Principal Investigator: Kodama Eiichi 東北大学, 医学(系)研究科(研究院), 講師 (50271151)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: HIV / 薬物相互作用 / 耐性 / 核酸誘導体 / ＨＩＶ

Outline of Final Research Achievements

In this study, we tried to expand our findings of ATP-medicated nucleotide excision inhibition, to biochemical, pharmacological, and structural aspects of DNA polymerases, via HIV reverse transcriptase as a model enzyme. We have established a novel assay system and screened over 5000 chemical compounds developed in the Tohoku University. Employing the identified several hits, structure-activity relation analysis is now in progress. In addition, we demonstrated that inhibitors for HIV reverse transcriptase appear to be experimentally suitable candidate to control differention process of mouse oocyte. Here we demonstrate that antiviral agents are useful for wide-range chemical biology tools as well as medical purpose.

Research Products

• [Journal Article] Use of a Biosynthetic Intermediate to Explore the Chemical Diversity of Pseudo-natural Fungal Polyketides (2015)
  • Author(s): T. Asai*, K. Tsukada, S. Ise, N. Shirata, M. Hashimoto, I. Fujii, K. Gomi, K. Nakagawara, E. N. Kodama, Y, Oshima
  • Journal Title: Nature Chem. Volume: 7 Issue: 9 Pages: 737-743
  • DOI: 10.1038/nchem.2308
  • Peer Reviewed
• [Journal Article] Inhibition of the DNA polymerase and RNase H activities of HIV-1 reverse transcriptase and HIV-1 replication by Brasenia schreberi (Junsai) and Petasites japonicus (Fuki) components. (2015)
  • Author(s): Tetsuro Hisayoshi, Mayu Shinomura, Kanta Yokokawa, Ikumi Kuze, Atsushi Konishi, Kumi Kawaji, Eiichi N. Kodama, Keishi Hata, Saori Takahashi, Satoru Nirasawa, Kiyoshi Yasukawa.
  • Journal Title: Journal of Natural Medicines Volume: in press Issue: 3 Pages: 432-440
  • DOI: 10.1007/s11418-015-0885-9
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of Vpr-binding derivative for use as a novel HIV-1 inhibitor. (2015)
  • Author(s): Hagiwara K, Ishii H, Murakami T, Takeshima SN, Chutiwitoonchai N, Kodama EN, Kawaji K, Kondoh Y, Honda K, Osada H, Tsunetsugu-Yokota Y, Suzuki M, Aida Y
  • Journal Title: PLoS One Volume: 10 Issue: 12 Pages: e0145573-e0145573
  • DOI: 10.1371/journal.pone.0145573
  • Peer Reviewed / Open Access
• [Journal Article] Histone chaperone CAF-1 mediates repressive histone modifications to protect preimplantation mouse embryos from endogenous retrotransposon. (2015)
  • Author(s): Hatanaka Y, Inoue K, Oikawa M, Kamimura S, Ogonuki N, Kodam E, Ohkawa Y, Tsukada Y, Ogura A.
  • Journal Title: Proc Natl Acad Sci USA Volume: 112 Issue: 47 Pages: 14641-14646
  • DOI: 10.1073/pnas.1512775112
  • Peer Reviewed / Open Access
• [Journal Article] Anti-HIV-1 activitydetermined byb-galactosidase activityin the multinuclear activation ofan indicator assay is comparable with that by a conventional focus counting method. (2015)
  • Author(s): Fusako Miyamoto, Kumi Kawaji, Shinya Oishi, Nobutaka Fujii, Mitsuo Kaku, and Eiichi N.Kodama.
  • Journal Title: Antiviral Chemistry and Chemotherapy Volume: 24（2） Issue: 2 Pages: 77-82
  • DOI: 10.1177/2040206615614164
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 4’-Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. (2014)
  • Author(s): Eleftherios Michailidis, Andrew D. Huber, Emily M. Ryan, Yee T. Ong, Maxwell D. Leslie, Kayla B. Matzek, Kamalendra Singh, Bruno Marchand, Ariel N. Hagedorn, Karen A. Kirby, Lisa C. Rohan, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, and Stefan G. Sarafianos.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 35 Pages: 24533-24548
  • DOI: 10.1074/jbc.m114.562694
  • Peer Reviewed
• [Journal Article] Current studies on chronic active Epstein-Barr virus infection in Japan. (2014)
  • Author(s): Fujiwara S, Kimura H, Imadome K, Arai A, Kodama, E, Morio T, Shimizu N, and Wakiguchi H.
  • Journal Title: Pediatr Int. Volume: 56 Issue: 2 Pages: 159-166
  • DOI: 10.1111/ped.12314
  • Peer Reviewed
• [Journal Article] Delayed emergence of HIV-1 variants resistant to 4’-ethynyl-2-fluoro-2’-deoxyadenosine: comparative sequential passage study with lamivudine, tenofovir, emtricitabine and BMS-986001 (2013)
  • Author(s): Kenji Maeda, Darshan V Desai, Manabu Aoki, Hirotomo Nakata, Eiichi N Kodama, Hiroaki Mitsuya
  • Journal Title: Antiviral Therapy Volume: 19 Issue: 2 Pages: 179-189
  • DOI: 10.3851/imp2697
  • Peer Reviewed / Open Access
• [Journal Article] Mechanism of Resistance to S138A Substituted Enfuvirtide and its Application to Peptide Design (2013)
  • Author(s): Kazuki Izumi, Kumi Kawaji, Fusasko Miyamoto, Kazuki Shimane, Kazuya Shimura, Yasuko Sakagami, Toshio Hattori, Kentaro Watanabe, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka, Mitsuo Kaku, Stefan G. Sarafianos, and Eiichi N. Kodama
  • Journal Title: International Journal of Biochemistry and Cell Biology Volume: 45 Pages: 908-915
• [Journal Article] HIV-1 resistance mechanism to an electrostatically constrained peptide fusion inhibitor that is active against T-20-resistant strains (2013)
  • Author(s): Kazuki Shimane, KumiKawaji, Fusako Miyamoto, Shinya Oishi, Kentaro Watanabe, YasukoSakagami, Nobutaka Fujii, Kazuya Shimura, Masao Matsuoka, Mitsuo Kaku, Stefan Sarafianos, and Eiichi Kodama
  • Journal Title: Antimicrobal Agents and Chemotherapy Volume: 57 Pages: 4035-4038
• [Journal Article] Hypersusceptibility Mechanism of Tenofovir-Resistant HIV to EFdA (2013)
  • Author(s): Eleftherios Michailidis, Emily M Ryan, Atsuko Hachiya, Karen A Kirby, Bruno Marchand, Maxwell D Leslie, Andrew D Huber, Yee T Ong, Jacob C Jackson, Kamalendra Singh, Eiichi N Kodama, Hiroaki Mitsuya, Michael A Parniak and Stefan G Sarafianos
  • Journal Title: Retrovirology Volume: 10 Issue: 1 Pages: 65-65
  • DOI: 10.1186/1742-4690-10-65
  • Peer Reviewed
• [Journal Article] Evaluation of combinations of 4'-ethynyl-2-fluoro-2'-deoxyadenosine with clinically used antiretroviral drugs (2013)
  • Author(s): Atsuko Hachiya, Aaron Reeve, Bruno Marchand, Eleftherios Michailidis, Yee Ong, Karen Kirby, Maxwell Leslie, Shinichi Oka, Eiichi Kodama, Lisa Rohan, Hiroaki Mitsuya, Michael Parniak, and Stefan Sarafianos
  • Journal Title: Antimicrobal Agents and Chemotherapy Volume: 57 Pages: 4554-4558
• [Journal Article] Sarafianos SG.Effects of substitutions at the 4' and 2 positions on the bioactivity of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (2013)
  • Author(s): Kirby KA, Michailidis E, Fetterly TL, Steinbach MA, Singh K, Marchand B, Leslie MD, Hagedorn AN, Kodama EN, Marquez VE, Hughes SH, Mitsuya H, Parniak MA
  • Journal Title: Antimicrobal Agents and Chemotherapy Volume: 57 Pages: 6254-6264
• [Presentation] Structural Basis of Inhibition and Resistance Mechanism to EFdA, a Highly Potent NRTI. (2015)
  • Author(s): Zhe Li, Karen Kirby, Bruno Marchand, Michailidis Eleftherios, Eiichi Kodama, Hiroaki Mitsuya, Michael Parniak, Stefan Sarafianos.
  • Organizer: The annual Conference on Retroviruses and Opportunistic Infections
  • Place of Presentation: シアトル・アメリカ
  • Year and Date: 2015-02-23 – 2015-02-26