コロナウイルス制圧のための新規膜融合阻害ペプチドの創出と合理的な設計法の確立

• Project/Area Number: 21K19366
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Tohoku University
• Principal Investigator: 児玉 栄一 東北大学, 災害科学国際研究所, 教授 (50271151)
• Co-Investigator(Kenkyū-buntansha): 大石 真也 京都薬科大学, 薬学部, 教授 (80381739)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: SARS-CoV-2 / 創薬 / 膜融合 / ヘリックス / ペプチド

Outline of Research at the Start

新型コロナウイルスに代表される高い病原性・感染性をもつ感染症の拡大は、医療だけでなく経済、そして日常生活にまで影響を及ぼす。本研究ではウイルスタンパクのごくわずか（ペプチド）を治療に利用できるかを検討するとともに、耐性ウイルスを誘導し、この耐性機序を創薬に応用する。この治療概念からタンパク工学と創薬学の融合を加速させ、新たな学問領域の発展に貢献する挑戦的な研究である。

Outline of Annual Research Achievements

新型コロナウイルスは、細胞侵入に重要な役割を果たすスパイクタンパクのC末端側にS2サブユニットをもつ。本研究では我々が確立したS2サブユニットを標的としたペプチド設計法とin vitro 耐性誘導を組み合わせ、１）設計-２）評価-３）耐性ウイルス誘導-４）耐性機序の解明-５）耐性機序を利用し、より強力で薬剤耐性を生じにくい阻害剤を効果的にかつ短期間に開発することを目標とした。研究期間内にふたつの効率的な抗ウイルス活性の評価方法を確立した。ひとつは、非感染系かつハイスループットなELISA法であり、3時間以内にその評価を可能とする。本法は細胞等を利用しないため、培養中に起こりうる標的細胞に対する毒性やペプチドの分解などを考慮せず、ヒットペプチドを同定しうる。もうひとつは、標的細胞としてVero細胞と感染性ウイルスを用い、より簡便で迅速なMTT色素法を組み合わせた培養評価系である。これらを駆使し、ヘリックス構造に必須の51残基の両端からアミノ酸を欠失させたペプチドを約２０合成し、ウイルス感染を抑制しうる重要な3か所のアミノ酸配列を同定することができた。ペプチド長を短くするためにこの3か所のうち2か所を有するペプチドを複数合成したが、一か所でも削除するとそのいずれでも活性が低下した。特にHR2領域中央にある部位は重要であり、アミノ酸置換で劇的に活性が低下した。これらのin vitroデータと構造予測AIであるAlphafold2を駆使し、効果発現と構造学的考察を加えて論文報告をした。本研究では、タンパク間相互作用解析、構造予測、感染実験を学理的に融合し、新型コロナウイルスをモデルとして抗ウイルス効果を有するペプチドを実際に同定することにより、迅速かつ安全に感染症治療ペプチド薬の開発を行う研究方針を確立できることを証明した。

Research Products

• [Journal Article] Relationships of Fat Mass Index and Fat-Free Mass Index with Low-Density Lipoprotein Cholesterol Levels in the Tohoku Medical Megabank Community-Based Cohort Study (2024)
  • Author(s): Takase Masato、Nakamura Tomohiro、Nakaya Naoki、Kogure Mana、Hatanaka Rieko、Nakaya Kumi、Chiba Ippei、Kanno Ikumi、Nochioka Kotaro、Tsuchiya Naho、Hirata Takumi、Obara Taku、Ishikuro Mami、Uruno Akira、Kobayashi Tomoko、Kodama Eiichi N、Hamanaka Yohei、Orui Masatsugu、Ogishima Soichi、Nagaie Satoshi、et al.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 31 Issue: 6 Pages: 979-1003
  • DOI: 10.5551/jat.64535
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2024-06-01
  • Peer Reviewed / Open Access
• [Journal Article] Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion (2024)
  • Author(s): Suzuki Satoshi、Kuroda Mio、Aoki Keisuke、Kawaji Kumi、Hiramatsu Yoshiki、Sasano Mina、Nishiyama Akie、Murayama Kazutaka、Kodama Eiichi N.、Oishi Shinya、Hayashi Hironori
  • Journal Title: RSC Chemical Biology Volume: 5 Issue: 2 Pages: 131-140
  • DOI: 10.1039/d3cb00166k
  • Peer Reviewed / Open Access
• [Journal Article] Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors (2024)
  • Author(s): Hirata Kazushige、Takahara Aoi、Suzuki Satoshi、Murakami Shumei、Kawaji Kumi、Nishiyama Akie、Sasano Mina、Shoji-Ueno Mariko、Usui Emiko、Murayama Kazutaka、Hayashi Hironori、Oishi Shinya、Kodama Eiichi N.
  • Journal Title: iScience Volume: 27 Issue: 2 Pages: 108961-108961
  • DOI: 10.1016/j.isci.2024.108961
  • Peer Reviewed / Open Access
• [Journal Article] Real-world effectiveness of full and booster mRNA vaccination for coronavirus disease 2019 against disease severity during the delta- and omicron-dominant phases: A propensity score-matched cohort study using the nationwide registry data in Japan (2024)
  • Author(s): Suzuki Tetsuya、Asai Yusuke、Tsuzuki Shinya、Nomoto Hidetoshi、Matsunaga Nobuaki、Kodama Eiichi N.、Hayakawa Kayoko、Ohmagari Norio
  • Journal Title: Journal of Microbiology, Immunology and Infection Volume: 57 Issue: 1 Pages: 20-29
  • DOI: 10.1016/j.jmii.2023.12.002
  • Peer Reviewed / Open Access
• [Journal Article] Improving diagnostic accuracy of blood culture-positive cases in a cancer center via an antimicrobial stewardship program and infectious disease consultations (2024)
  • Author(s): Itoh Naoya、Akazawa Nana、Kawabata Takanori、Yamaguchi Makoto、Kodama Eiichi N.、Ohmagari Norio
  • Journal Title: Scientific Reports Volume: 14 Issue: 1 Pages: 2869-2869
  • DOI: 10.1038/s41598-024-53543-w
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of the full-length hepatitis B virus core protein and its capsid formation (2024)
  • Author(s): Aoki Keisuke、Tsuda Shugo、Ogata Naoko、Kataoka Michiyo、Sasaki Jumpei、Inuki Shinsuke、Ohno Hiroaki、Watashi Koichi、Yoshiya Taku、Oishi Shinya
  • Journal Title: Organic &; Biomolecular Chemistry Volume: 22 Issue: 11 Pages: 2218-2225
  • DOI: 10.1039/d3ob02099a
  • Peer Reviewed / Open Access
• [Journal Article] Association of Central Blood Pressure and Carotid Intima Media Thickness with New-Onset Hypertension in People with High Normal Blood Pressure (2023)
  • Author(s): Tokioka Sayuri、総数25人中19番目
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 12 Pages: 1905-1916
  • DOI: 10.5551/jat.64151
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-12-01
  • Peer Reviewed / Open Access
• [Journal Article] Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study (2023)
  • Author(s): Takase Masato、総数28人中17番目
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 12 Pages: 1950-1965
  • DOI: 10.5551/jat.64425
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-12-01
  • Peer Reviewed / Open Access
• [Journal Article] Carotid Intima Media Thickness and Risk Factor for Atherosclerosis: Tohoku Medical Megabank Community-Based Cohort Study (2023)
  • Author(s): Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 10 Pages: 1471-1482
  • DOI: 10.5551/jat.64039
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-10-01
  • Peer Reviewed / Open Access
• [Journal Article] The Association of Lung Function and Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study (2023)
  • Author(s): Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 8 Pages: 1022-1044
  • DOI: 10.5551/jat.63826
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Mental Health Problems among University Students under the Prolonged COVID-19 Pandemic in Japan: A Repeated Cross-Sectional Survey (2023)
  • Author(s): Seto Moe、Usukura Hitomi、Kunii Yasuto、Hamaie Yumiko、Kodama Eiichi N.、Makino Yuko、Kinouchi Yoshitaka、Ito Chihiro、Ikeda Tadayoshi、Tomita Hiroaki
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 260 Issue: 1 Pages: 1-11
  • DOI: 10.1620/tjem.2023.J012
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Circulating Extracellular Vesicle Levels in Patients with Coronavirus Disease 2019 Coagulopathy: A Prospective Cohort Study (2023)
  • Author(s): Yudai Iwasaki, Yusuke Takei, Mitsuhiro Yamada, Shigekazu Sugino, Koji Saito, Tetsuji Aoyagi, Kengo Oshima, Hajime Kanamori, Hiroaki Baba, Kentarou Takei, Koichi Tokuda, Eichi N. Kodama, Tetsuro Kamo, Tadashi Kamio, Takehiko Kasai, Satoru Ogawa, Masanori Yamauchi.
  • Journal Title: Journal of Clinical Medicine Volume: 12 Issue: 10 Pages: 3460-3460
  • DOI: 10.3390/jcm12103460
  • Peer Reviewed / Open Access
• [Journal Article] Rapid Detection of SARS-CoV-2 RNA Using Reverse Transcription Recombinase Polymerase Amplification (RT-RPA) with Lateral Flow for N-Protein Gene and Variant-Specific Deletion-Insertion Mutation in S-Protein Gene (2023)
  • Author(s): Malaga Jose L.、総数24人中21番目
  • Journal Title: Viruses Volume: 15 Issue: 6 Pages: 1254-1254
  • DOI: 10.3390/v15061254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of oral macrolide prescriptions in Japan using a retrospective claims database, 2013-2018 (2023)
  • Author(s): Ide Satoshi、Ishikane Masahiro、Aoyagi Kensuke、Ono Akane、Asai Yusuke、Tsuzuki Shinya、Kusama Yoshiki、Gu Yoshiaki、Kodama Eiichi、Ohmagari Norio
  • Journal Title: PLOS ONE Volume: 18 Issue: 6 Pages: 27297-287297
  • DOI: 10.1371/journal.pone.0287297
  • Peer Reviewed / Open Access
• [Journal Article] HIV-1 Resistance to Islatravir/Tenofovir Combination Therapy in Wild-Type or NRTI-Resistant Strains of Diverse HIV-1 Subtypes (2023)
  • Author(s): Cilento Maria E.、Wen Xin、Reeve Aaron B.、Ukah Obiaara B.、Snyder Alexa A.、Carrillo Ciro M.、Smith Cole P.、Edwards Kristin、Wahoski Claudia C.、Kitzler Deborah R.、Kodama Eiichi N.、Mitsuya Hiroaki、Parniak Michael A.、Tedbury Philip R.、Sarafianos Stefan G.
  • Journal Title: Viruses Volume: 15 Issue: 10 Pages: 1990-1990
  • DOI: 10.3390/v15101990
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The risk of withdrawal from hypertension treatment in coastal areas after the Great East Japan Earthquake: the TMM CommCohort Study (2023)
  • Author(s): Hatanaka Rieko、Nakaya Naoki、Kogure Mana、Nakaya Kumi、Chiba Ippei、Kanno Ikumi、Hashimoto Hideaki、Nakamura Tomohiro、Nochioka Kotaro、Obara Taku、Hamanaka Yohei、Sugawara Junichi、Kobayashi Tomoko、Uruno Akira、Kodama Eiichi N.、Fuse Nobuo、Kuriyama Shinichi、Hozawa Atsushi
  • Journal Title: Hypertension Research Volume: 46 Issue: 12 Pages: 2718-2728
  • DOI: 10.1038/s41440-023-01454-0
  • Peer Reviewed / Open Access
• [Journal Article] The association between depressive symptoms and masked hypertension in participants with normotension measured at research center (2023)
  • Author(s): Tokioka Sayuri、総数25人中19番目
  • Journal Title: Hypertension Research Volume: 47 Issue: 3 Pages: 586-597
  • DOI: 10.1038/s41440-023-01484-8
  • Peer Reviewed / Open Access
• [Journal Article] Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: An interrupted time-series analysis (2023)
  • Author(s): Itoh Naoya、Kawabata Takanori、Akazawa Nana、Kawamura Daichi、Murakami Hiromi、Ishibana Yuichi、Kodama Eiichi N.、Ohmagari Norio
  • Journal Title: PLOS ONE Volume: 18 Issue: 2 Pages: e0281518-e0281518
  • DOI: 10.1371/journal.pone.0281518
  • Peer Reviewed / Open Access
• [Journal Article] Establishing an Accurate and Sensitive In Vitro Drug Screening System for Human Adenovirus Infection with Human Corneal Cells (2023)
  • Author(s): Mina Sasano, Hironori Hayashi, Kumi Kawaji, Emiko Usui, Eiich N Kodama.
  • Journal Title: Virology Volume: 581 Pages: 34-38
  • DOI: 10.1016/j.virol.2023.02.005
  • Peer Reviewed
• [Journal Article] Nasopharyngeal SARS-CoV-2 is not dispersed by high-flow nasal cannula. (2023)
  • Author(s): Tetsuya Suzuki, Shinichiro Morioka, Kei Yamamoto, Sho Saito, Shun Iida, Katsuji Teruya, Jin Takasaki, Masayuki Hojo, Kayoko Hayakawa, Satoshi Kutsuna, Sho Miyamoto, Seiya Ozono, Tadaki Suzuki, Eiichi N Kodama, Norio Ohmagari.
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 2669-2669
  • DOI: 10.1038/s41598-023-29740-4
  • Peer Reviewed / Open Access
• [Journal Article] Effects of infectious disease consultation and antimicrobial stewardship program at a Japanese cancer center: An interrupted time-series analysis (2022)
  • Author(s): Itoh Naoya、Akazawa Nana、Kanawaku Eri、Murakami Hiromi、Ishibana Yuichi、Kawamura Daichi、Kawabata Takanori、Mori Keita、Kodama Eiichi N.、Ohmagari Norio
  • Journal Title: PLOS ONE Volume: 17 Issue: 1 Pages: e0263095-e0263095
  • DOI: 10.1371/journal.pone.0263095
  • Peer Reviewed / Open Access
• [Journal Article] Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602 (2022)
  • Author(s): Ohata Yoshitsugu、Tomonaga Mitsunori、Watanabe Yasuo、Tomura Keiko、Kimura Koji、Akaki Tatsuo、Adachi Kaoru、Kodama Eiichi N.、Matsuzaki Yuji、Hayashi Hironori
  • Journal Title: Journal of Virology Volume: 96 Issue: 6
  • DOI: 10.1128/jvi.01843-21
  • Peer Reviewed / Open Access
• [Journal Article] Factors associated with prolonged psychological distress among nurses and physicians engaged in COVID-19 patient care in hospitals in Singapore and Japan. (2022)
  • Author(s): Shinichiro Morioka, Ban Hock Tan, Hiroe Kikuchi, Yusuke Asai, Tetsuya Suzuki, Shinobu Ashida, Satoshi Kutsuna, Sho Saito, Kayoko Hayakawa, Thuan Tong Tan, Eiichi Kodama, Norio Ohmagari.
  • Journal Title: Frontiers in Psychiatry Volume: 13 Pages: 781796-781796
  • DOI: 10.3389/fpsyt.2022.781796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serine hydroxymethyltransferase as a potent target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors. (2022)
  • Author(s): Yuko Makino, Chihiro Oe, Kazuya Iwama, Satoshi Suzuki, Akie Nishiyama, Kazuya Hasegawa, Haruka Okuda, Kazushige Hirata, Mariko Ueno, Kumi Kawaji, Mina Sasano, Emiko Usui, Toshiaki Hosaka, Yukako Yabuki, Mikako Shirouzu, Makoto Katsumi, Kazutaka Murayama, Hironori Hayashi, Eiichi N. Kodama.
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 619-619
  • DOI: 10.1038/s42003-022-03555-x
  • Peer Reviewed / Open Access
• [Journal Article] Change in Use of Pediatric Oral Antibiotics in Japan: Pre and post AMR action plan. (2022)
  • Author(s): Noriko Iwamoto, Naho Morisaki, Kazuhiro Uda, Masashi Kasai, Eiichi Kodama, Norio Ohmagari, Isao Miyairi.
  • Journal Title: Pediatrics International Volume: 64 Issue: 1
  • DOI: 10.1111/ped.15197
  • Peer Reviewed / Open Access
• [Journal Article] Interferon lambda 3 in the early phase of coronavirus disease-19 can predict disease progression. (2022)
  • Author(s): Tetsuya Suzuki. Noriko Iwamoto, Shinya Tsuzuki, Yuko Kakumoto, Michiyo Suzuki, Shinobu Ashida, et. al.
  • Journal Title: European Journal of Clinical Investigation Volume: 52 Issue: 9
  • DOI: 10.1111/eci.13808
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of Sputum Specimens and Nasopharyngeal Swab Specimens for Diagnosis of Acute Human Metapneumovirus-related Lower Respiratory Tract Infections in Adults. (2022)
  • Author(s): Takehiro Yajima, Hiroshi Takahashi, Nozomu Kimura, Kosuke Sato, Daisuke Jingu, Satoshi Ubukata, Makoto Shoji, Hiroshi Watanabe, Eiichi N. Kodama, Hidekazu Nishimura.
  • Journal Title: Journal of Clinical Virology Volume: 154 Pages: 105238-105238
  • DOI: 10.1016/j.jcv.2022.105238
  • Peer Reviewed
• [Journal Article] Lessons learned from an outbreak of COVID-19 in the head and neck surgery ward of a Japanese cancer center during the sixth wave by Omicron. (2022)
  • Author(s): Naoya Itoh, Nana Akazawa, Masahiro Ishikane, Takanori Kawabata, Daichi Kawamura, Tomoyuki Chikusa, Eiichi N Kodama, Norio Ohmagari.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 28 Issue: 12 Pages: 1610-1615
  • DOI: 10.1016/j.jiac.2022.08.010
  • Peer Reviewed
• [Journal Article] Surveillance and risk assessment of health screening for vaccine-preventable diseases among international students in Japan: A cross-sectional study in 2020 (2022)
  • Author(s): Hanako Takahata, Kazunari Onishi, Hidetoshi Nomoto, Noriko Iwamoto,Kuniyoshi Hayashi, Narumi Hori, Satoshi Kutsuna, Eiichi N. Kodama, Norio Ohmagari.
  • Journal Title: Human Vaccines & Immunotherapeutics Volume: 18 Issue: 6 Pages: 2136914-2136914
  • DOI: 10.1080/21645515.2022.2136914
  • Peer Reviewed
• [Journal Article] Impact of the COVID-19 pandemic on racial and ethnic minorities in Japan. (2022)
  • Author(s): Hidetoshi Nomoto, Yusuke Asai, Kayoko Hayakawa, Nobuaki Matsunaga, Satoshi Kutsuna, Eiichi N. Kodama, Norio Ohmagari.
  • Journal Title: Epidemiology and Infection Volume: 150 Pages: 1-9
  • DOI: 10.1017/s0950268822001674
  • Peer Reviewed / Open Access
• [Journal Article] Disseminated tuberculosis with paradoxical reactions caused by a Mycobacterium tuberculosis strain belonging to the Indo-Oceanic lineage: An imported case in Japan (2022)
  • Author(s): Oshima Kengo、Nakajima Chie、Hirata Kazushige、Hayashi Hironori、Kodama Eiichi N.、Fukushima Yukari、Suzuki Yasuhiko、Kanamori Hajime、Baba Hiroaki、Aoyagi Tetsuji、Tokuda Koichi、Kaku Mitsuo
  • Journal Title: Journal of Infection and Chemotherapy Volume: S1341-321X Issue: 7 Pages: 00048-4
  • DOI: 10.1016/j.jiac.2022.02.008
  • Peer Reviewed
• [Journal Article] Development of robust isothermal RNA amplification assay for lab-free testing of RNA viruses (2021)
  • Author(s): Biyani Radhika、Sharma Kirti、Kojima Kenji、Biyani Madhu、Sharma Vishnu、Kumawat Tarun、Juma Kevin Maafu、Yanagihara Itaru、Fujiwara Shinsuke、Kodama Eiichi、Takamura Yuzuru、Takagi Masahiro、Yasukawa Kiyoshi、Biyani Manish
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 15997-15997
  • DOI: 10.1038/s41598-021-95411-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 麻疹ウイルス膜融合阻害ペプチドの構造最適化研究 (2022)
  • Author(s): 山口夕貴, 髙原葵, 青木啓輔, 中津亨, 平田和成, 鈴木聡志, 林宏典, 河治久実, 井貫晋輔, 大野浩章, 加藤博章, 村山和隆, 児玉栄一, 大石真也
  • Organizer: 第39回メディシナルケミストリーシンポジウム