Development of a bacteria-derived ACE2-like enzyme as a therapeutics for treating cardiovascular diseases

• Project/Area Number: 20K21566
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Akita University
• Principal Investigator: Kuba Keiji 秋田大学, 医学系研究科, 教授 (10451915)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: ACE2 / B38-CAP / ARDS / 心不全 / SARS-CoV-2 / COVID-19 / 敗血症 / 急性肺傷害 / 急性呼吸窮迫症候群 / 血管透過性 / アンジオテンシン / 進化

Outline of Research at the Start

アンジオテンシン変換酵素２(ACE2)は、高血圧や心不全などの循環器疾患あるいは急性呼吸窮迫症候群(ARDS)などの呼吸器疾患の病態を改善させる作用を持つが、創薬に応用するためにはコストと時間がかかるために困難となっている。最近、私達は、新種の細菌がもつ酵素B38-CAPがACE2活性を持つことを見出した。B38-CAPは大腸菌の蛋白質発現系で生産できることから、創薬上でのメリットが予想された。そこで、本研究では、このACE2様酵素B38-CAPが生体内で循環器疾患やARDSの病態を改善するかを検討し、収斂進化のACE2蛋白製剤による循環器・呼吸器疾患の治療法を開発する。

Outline of Final Research Achievements

The discovery of the ACE2-like enzyme B38-CAP based on the concept of convergent evolution in microorganisms suggests that it can be an alternative to the recombinant ACE2 protein, which is costly and time-consuming for mass production. We thus conducted research for the therapeutic application of B38-CAP, which can be prepared in large quantities very quickly. Specifically, we investigated the therapeutic effects of ACE2-like enzyme B38-CAP in an animal model of acute cardiovascular respiratory failure and COVID-19. The results showed that B38-CAP prevented acute cardiovascular respiratory failure due to sepsis and aspiration pneumonia, as well as the aggravation of COVID-19 pneumonia. Therefore, we were able to establish the basis of practical treatment techniques for acute cardiovascular respiratory failure by using ACE2-like enzymes.

Academic Significance and Societal Importance of the Research Achievements

本研究成果により、ACE2様酵素B38-CAPを用いた心不全、ARDS/急性呼吸不全、敗血症やCOVID-19に対する治療への応用が期待できる。とりわけACE2酵素が大腸菌タンパク質生産系で調製し蛋白調製の効率化を図れることに加えて、他の蛋白製剤についてもジェネリック蛋白製剤の概念を応用することが期待される。

Research Products

• [Int'l Joint Research] University of British Columbia(カナダ)
• [Int'l Joint Research] The University of Hong Kong(中国)
• [Int'l Joint Research] Ludwig Maximilians University of Munich(ドイツ)
• [Int'l Joint Research] The University of Hong Kong(中国)
• [Journal Article] ACE2の循環器疾患および感染症における意義 (2022)
  • Author(s): 久場敬司
  • Journal Title: CARDIAC PRACTICE Volume: 2 Pages: 36-41
• [Journal Article] Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19 (2021)
  • Author(s): Kuba Keiji、Yamaguchi Tomokazu、Penninger Josef M.
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 732690-732690
  • DOI: 10.3389/fimmu.2021.732690
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury (2021)
  • Author(s): Yamaguchi T, Hoshizaki M, Minato T, Nirasawa S, Asaka MN, Niiyama M, Imai M, Uda A, Chan JF, Takahashi S, An J, Saku A, Nukiwa R, Utsumi D, Kiso M, Yasuhara A, Poon VK, Chan CC, Fujino Y, Motoyama S, Nagata S, Penninger JM, Kamada H, Yuen KY, Kamitani W, Maeda K, Kawaoka Y, Yasutomi Y, Imai Y, Kuba Keiji
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 6791-6791
  • DOI: 10.1038/s41467-021-27097-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Highly susceptible SARS-CoV-2 model in CAG promoter?driven hACE2-transgenic mice (2021)
  • Author(s): Asaka Masamitsu N.、Utsumi Daichi、Kamada Haruhiko、Nagata Satoshi、Nakachi Yutaka、Yamaguchi Tomokazu、Kawaoka Yoshihiro、Kuba Keiji、Yasutomi Yasuhiro
  • Journal Title: JCI Insight Volume: 6 Issue: 19 Pages: 1-2
  • DOI: 10.1172/jci.insight.152529
  • Peer Reviewed / Open Access
• [Journal Article] Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection (2021)
  • Author(s): Kim Kwang Su、Iwanami Shoya、Oda Takafumi、Fujita Yasuhisa、Kuba Keiji、Miyazaki Taiga、Ejima Keisuke、Iwami Shingo
  • Journal Title: Life Science Alliance Volume: 4 Issue: 10 Pages: e202101049-e202101049
  • DOI: 10.26508/lsa.202101049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suv4-20h2 protects against influenza virus infection by suppression of chromatin loop formation (2021)
  • Author(s): Shiimori Masami、Ichida Yu、Nukiwa Ryota、Sakuma Toshie、Abe Haruka、Kajitani Rei、Fujino Yuji、Kikuchi Akira、Kawamura Takeshi、Kodama Tatsuhiko、Toyooka Shinichi、Shirahige Katsuhiko、Schotta Gunnar、Kuba Keiji、Itoh Takehiko、Imai Yumiko
  • Journal Title: iScience Volume: 24 Issue: 6 Pages: 102660-102660
  • DOI: 10.1016/j.isci.2021.102660
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SARS-CoV-2とRAS/ACE2 (2021)
  • Author(s): 久場敬司
  • Journal Title: Thrombosis Medicine Volume: 11
• [Journal Article] COVID-19の発症機序 (2021)
  • Author(s): 久場敬司
  • Journal Title: 月刊心臓 Volume: 53 Pages: 1-1
• [Journal Article] Clonal hematopoiesis in adult pure red cell aplasia (2021)
  • Author(s): Fujishima N、Kohmaru J、Koyota S、Kuba K、Saga T、Omokawa A、Moritoki Y、Ueki S、Ishida F、Nakao S、Matsuda A、Ohta A、Tohyama K、Yamasaki H、Usuki K、Nakashima Y、Sato S、Miyazaki Y、Nannya Y、Ogawa S、Sawada K、Mitani K、Hirokawa M
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 2253-2253
  • DOI: 10.1038/s41598-021-81890-5
  • Peer Reviewed / Open Access
• [Journal Article] 種を超えて保存されたACE2様酵素B38-CAPの循環器疾患への治療応用 (2021)
  • Author(s): 久場敬司
  • Journal Title: BIO Clinica Volume: 36 Pages: 228-230
• [Journal Article] Virus database annotations assist in tracing information on patients infected with emerging pathogens (2020)
  • Author(s): Akiko Nakashima, Mitsue Takeya, Keiji Kuba, Makoto Takano, Noriyuki Nakashima
  • Journal Title: Informatics in Medicine Unlocked Volume: 100442 Pages: 100442-100442
  • DOI: 10.1016/j.imu.2020.100442
  • Peer Reviewed / Open Access
• [Journal Article] Eosinophils promote corneal wound healing via the 12/15‐lipoxygenase pathway (2020)
  • Author(s): Ogawa Mamoru、Ishihara Tomoaki、Isobe Yosuke、Kato Taiga、Kuba Keiji、Imai Yumiko、Uchino Yuichi、Tsubota Kazuo、Arita Makoto
  • Journal Title: The FASEB Journal Volume: 34 Issue: 9 Pages: 12492-12501
  • DOI: 10.1096/fj.202000483r
  • Peer Reviewed / Open Access
• [Journal Article] The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation (2020)
  • Author(s): Takahashi Akinori、Suzuki Toru、Soeda Shou、Takaoka Shohei、Kobori Shungo、Yamaguchi Tomokazu、Mohamed Haytham Mohamed Aly、Yanagiya Akiko、Abe Takaya、Shigeta Mayo、Furuta Yasuhide、Kuba Keiji、Yamamoto Tadashi
  • Journal Title: Life Science Alliance Volume: 3 Issue: 5 Pages: 1-19
  • DOI: 10.26508/lsa.201900494
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] m6A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis (2020)
  • Author(s): Nagaki Yushi、Motoyama Satoru、Yamaguchi Tomokazu、Hoshizaki Midori、Sato Yusuke、Sato Teruki、Koizumi Yukio、Wakita Akiyuki、Kawakita Yuta、Imai Kazuhiro、Nanjo Hiroshi、Watanabe Hiroyuki、Imai Yumiko、Minamiya Yoshihiro、Kuba Keiji
  • Journal Title: Genes to Cells Volume: 25 Issue: 8 Pages: 547-561
  • DOI: 10.1111/gtc.12792
  • Peer Reviewed / Open Access
• [Journal Article] ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury (2020)
  • Author(s): Minato T, Hoshizaki M, Yamaguchi T, Nirasawa S, Asaka MN, Kamada H, Yuen KM, Kawaoka Y, Yasutomi Y, Imai Y, Kuba K, et al.
  • Journal Title: researchsquare.com/article/rs-124634/v1 Volume: -
  • DOI: 10.21203/rs.3.rs-124634/v1
  • Open Access / Int'l Joint Research
• [Journal Article] 新規微生物由来酵素B38-CAPはACE2活性により高血圧と心不全を改善する (2020)
  • Author(s): 湊隆文，久場敬司
  • Journal Title: 実験医学 Volume: 38 Pages: 2371-2374
• [Journal Article] 微生物由来の新規ACE2様酵素による循環器疾患症状の改善 (2020)
  • Author(s): 久場敬司，韮澤悟
  • Journal Title: BIOSCIENCE & INDUSTRY Volume: 78 Pages: 512-513
• [Presentation] COVID-19のARDS/急性肺傷害に対するACE2酵素活性の治療効果 (2021)
  • Author(s): 久場敬司
  • Organizer: 第１７回霊長類医科学フォーラム
  • Invited
• [Presentation] ACE2酵素活性による COVID-19 急性肺傷害の治療 (2021)
  • Author(s): 久場敬司
  • Organizer: 第94回日本生化学会大会シンポジウム1S10e
• [Presentation] ACE2酵素B38-CAPの循環呼吸器疾患への治療応用 (2021)
  • Author(s): 久場敬司
  • Organizer: 創薬薬理フォーラム 第69回談話会
  • Invited
• [Presentation] CCR4-NOT Deadenylase Complex Controls the Expression of Autophagy Genes and Prevents Atg7-Dependent Cell Death in the Heart (2021)
  • Author(s): 山口 智和, 鈴木 享, 佐藤 輝紀, 高橋 明格, 山本 雅, 今井 由美子, 久場 敬司
  • Organizer: 第85回 日本循環器学会学術集会
• [Presentation] Suppression of SARS-CoV-2-induced lung injury by ACE2-like carboxypeptidase B38-CAP in COVID-19 mouse model (2021)
  • Author(s): Tomokazu Yamaguchi, Takafumi Minato, Midori Hoshizaki, Masamitsu N Asaka, Satoru Nirasawa, Mayumi Niiyama, Masaki Imai, Saori Takahashi, Daichi Utsumi, Jianbo An, Satoshi Nagata, Haruhiko Kamada, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai, Keiji Kuba
  • Organizer: 第94回 日本薬理学会
• [Presentation] ACE2酵素活性によるCOVID-19急性肺傷害の治療 (2021)
  • Author(s): 久場敬司
  • Organizer: 第5回理論免疫学ワークショップ
• [Presentation] 呼吸循環器疾患とRNA制御因子 (2020)
  • Author(s): 久場敬司
  • Organizer: Cardiology Research & Clinical seminar
• [Presentation] m6A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis. (2020)
  • Author(s): Yushi Nagaki, Keiji Kuba
  • Organizer: 第79回 日本癌学会
• [Presentation] 微生物由来のACE2様酵素B38-CAPはマウスにおける 心臓のリモデリングと機能不全を改善する (2020)
  • Author(s): 湊 隆文, 山口 智和, 佐藤 輝紀, 韮澤 悟, 今井 由美子, 高橋 砂織, 渡邊 博之, 久場 敬司
  • Organizer: 第71回 日本薬理学会北部会
• [Presentation] B38-CAP is a bacteria-derived carboxypeptidase which resembles SARS-CoV-2 receptor ACE2 enzyme activity and suppresses hypertension and cardiac dysfunction in mice (2020)
  • Author(s): Teruki Sato, Takafumi Minato, Satoru Nirasawa, Tomokazu Yamaguchi, Hiroyuki Watanabe, Yumiko Imai, Saori Takahashi, Keiji Kuba
  • Organizer: NIPS International meeting, HOLISTIC UNDERSTANDING OF CARDIOVASCULAR SYSTEM BY MECHANISTIC ANALYSIS OF PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 原核微生物由来ポリペプチドを含有する肺損傷および障害を処置または予防するための医薬組成物 (2020)
  • Inventor(s): 久場敬司、今井由美子
  • Industrial Property Rights Holder: 秋田大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020