Development of the novel HIV eradication method

• Project/Area Number: 19K23802
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Tateishi Hiroshi 熊本大学, 大学院生命科学研究部(薬), 特任助教 (50846011)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: HIV / Gag蛋白質 / MAドメイン / L-HIPPO / Lock-in and apoptosis / HIV-1 / Gag-MA / IP6 / Lock in and apoptosis / HIV Gag / プロドラッグ

Outline of Research at the Start

今日のエイズウイルス(HIV)感染症治療の最終目標は、体内からの潜伏感染細胞の完全除去である。近年、新しい治療法として、潜伏感染細胞を排除することを目的としたKick and Kill療法が行われているがKillの段階が十分でない。申請者は、ウイルス放出を阻害する非天然型イノシトールリン脂質誘導体L-HIPPOを創製し、Killの新たな方法としてL-HIPPOを用いた細胞死誘導法“Lock-in and apoptosis”法を開発した。本研究ではこの“Lock-in and apoptosis”を用い、Kick and Kill療法を発展させて臨床使用を目指す。

Outline of Final Research Achievements

In this study, we aimed to eradicate latently infected cells using the Lock-in and apoptosis method, and investigated the binding form of L-HIPPO and MA domain, and synthesis of prodrug derivative.
First, in order to check the binding form, about 600 types of crystallization conditions were examined by the vapor diffusion method. Although crystals were obtained, no L-HIPPO binding was observed. Currently, due to carry out crystallization by the lipid cubic phase method, purification of myristoylated MA protein (Myr-MA) and Myr-Gag has been started and obtained high-purity protein. On the other hand, we synthesized prodrug L-HIPPO and confirmed the virus release inhibitory effect. we succeeded in improving the membrane permeability. Induction of cell death in latently infected cells is currently confirmed.

Academic Significance and Societal Importance of the Research Achievements

多剤併用療法（ART）の導入によりHIV感染症は不治の病からコントロール可能な慢性疾患と捉えられるまでになった。しかしながら、現在の治療法では完治しないため一生薬を飲み続ける必要があり、その結果、副作用や合併症などが見られるようになった。実際に、多施設コホート研究によりHIV 感染者でART 治療群では、非HIV 感染者に比して約4 倍糖尿病の罹患率が高くなるという報告もある。HIVの完治が求められているが、本研究にて開発中であるLock-in and apoptosis法は、HIVの根絶に結びつくものと期待される。

Research Products

• [Journal Article] Design and synthesis of novel quinoline/chalcone/1,2,4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAFV600E kinases (2021)
  • Author(s): Mohassab Aliaa M.、Hassan Heba A.、Abdelhamid Dalia、Gouda Ahmed M.、Youssif Bahaa G.M.、Tateishi Hiroshi、Fujita Mikako、Otsuka Masami、Abdel-Aziz Mohamed
  • Journal Title: Bioorganic Chemistry Volume: 106 Pages: 104510-104510
  • DOI: 10.1016/j.bioorg.2020.104510
  • Peer Reviewed
• [Journal Article] Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M (2021)
  • Author(s): Kamo Masahiro、Ito Miu、Toma Tsugumasa、Gotoh Haruna、Shimozono Rie、Nakagawa Riko、Koga Ryoko、Monde Kazuaki、Tateishi Hiroshi、Misumi Shogo、Otsuka Masami、Fujita Mikako
  • Journal Title: Bioorganic Chemistry Volume: 107 Pages: 104627-104627
  • DOI: 10.1016/j.bioorg.2021.104627
  • Peer Reviewed
• [Journal Article] The stability of HIV-2 Vpx and Vpr proteins is regulated by the presence or absence of zinc-binding sites and poly-proline motifs with distinct roles (2020)
  • Author(s): Shimagaki Kazunori、Koga Ryoko、Fujino Haruna、Ahagon Ami、Tateishi Hiroshi、Otsuka Masami、Yamaguchi Yoshihiro、Fujita Mikako
  • Journal Title: Journal of General Virology Volume: 101 Issue: 9 Pages: 997-1007
  • DOI: 10.1099/jgv.0.001456
  • Peer Reviewed
• [Journal Article] Structure activity study of S-trityl-cysteamine dimethylaminopyridine derivatives as SIRT2 inhibitors: Improvement of SIRT2 binding and inhibition. (2020)
  • Author(s): Radwan, M.O., Ciftci, H.I., Ali, T.F.S., Koga, R., Tateishi, H., Nakata, A., Ito, A., Yoshida, M., Fujita, M., Otsuka, M.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 30(19) Issue: 19 Pages: 127458-127458
  • DOI: 10.1016/j.bmcl.2020.127458
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors (2020)
  • Author(s): Belgin Sever, Mehlika Dilek Altintop, Ahmet Ozdemir, Gulsen Akalin Ciftci, Doha E. Ellakwa, Hiroshi Tateishi, Mohamed O. Radwan, Mahmoud A. A. Ibrahim, Masami Otsuka, Mikako Fujita, Halil I. Ciftci and Taha F. S. Ali
  • Journal Title: Molecules Volume: 25 Issue: 21 Pages: 5190-5190
  • DOI: 10.3390/molecules25215190
  • Peer Reviewed / Open Access
• [Journal Article] Interruption of Vif/Elongin C interaction: In silico and experimental elucidation of the underlying molecular mechanism of benzimidazole-based APOBEC3G stabilizers (2020)
  • Author(s): Radwan Mohamed O.、Takaya Daisuke、Koga Ryoko、Iwamaru Kana、Tateishi Hiroshi、Ali Taha F.S.、Takaori-Kondo Akifumi、Otsuka Masami、Honma Teruki、Fujita Mikako
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 28 Issue: 8 Pages: 115409-115409
  • DOI: 10.1016/j.bmc.2020.115409
  • Peer Reviewed
• [Journal Article] HSP70 induction by bleomycin metal core analogs (2020)
  • Author(s): Ali Taha F.S.、Taira Naomi、Iwamaru Kana、Koga Ryoko、Kamo Masahiro、Radwan Mohamed O.、Tateishi Hiroshi、Kurosaki Hiromasa、Abdel-Aziz Mohamed、Abuo-Rahma Gamal El-Din A.A.、Beshr Eman A.M.、Otsuka Masami、Fujita Mikako
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 30 Issue: 7 Pages: 127002-127002
  • DOI: 10.1016/j.bmcl.2020.127002
  • Peer Reviewed
• [Journal Article] Antileukemic Activity of Twig Components of Caucasian Beech in Turkey (2019)
  • Author(s): Shida Wataru、Tateishi Hiroshi、Tahara Yurika、Fujita Mikako、Husham Majeed Alsaadi Doaa、Watanabe Masato、Koga Ryoko、Radwan Mohamed O.、Ciftci Halil I.、Gezici Sevgi、Kurauchi Yuki、Katsuki Hiroshi、Otsuka Masami、Sugimura Koji、Wada Mikiyo、Sekeroglu Nazim、Watanabe Takashi
  • Journal Title: Molecules Volume: 24 Issue: 21 Pages: 3850-3850
  • DOI: 10.3390/molecules24213850
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity (2019)
  • Author(s): I. Ciftci Halil、O. Radwan Mohamed、E. Ozturk Safiye、Ulusoy N. Gokce、Sozer Ece、E. Ellakwa Doha、Ocak Zeynep、Can Mustafa、F.S. Ali Taha、I. Abd-Alla Howaida、Yayli Nurettin、Tateishi Hiroshi、Otsuka Masami、Fujita Mikako
  • Journal Title: Molecules Volume: 24 Issue: 19 Pages: 3535-3535
  • DOI: 10.3390/molecules24193535
  • Peer Reviewed / Open Access
• [Journal Article] Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement (2019)
  • Author(s): Radwan Mohamed O.、Ciftci Halil I.、Ali Taha F. S.、Ellakwa Doha E.、Koga Ryoko、Tateishi Hiroshi、Nakata Akiko、Ito Akihiro、Yoshida Minoru、Okamoto Yoshinari、Fujita Mikako、Otsuka Masami
  • Journal Title: Molecules Volume: 24 Issue: 18 Pages: 3295-3295
  • DOI: 10.3390/molecules24183295
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-cancer activity of the cell membrane-permeable phytic acid prodrug (2019)
  • Author(s): Masunaga Takuya、Murao Naoki、Tateishi Hiroshi、Koga Ryoko、Ohsugi Takeo、Otsuka Masami、Fujita Mikako
  • Journal Title: Bioorganic Chemistry Volume: 92 Pages: 103240-103240
  • DOI: 10.1016/j.bioorg.2019.103240
  • Peer Reviewed
• [Journal Article] Minimum structural requirements for inhibitors of the zinc finger protein TRAF6 (2019)
  • Author(s): Radwan Mohamed O.、Koga Ryoko、Hida Tomohiro、Ejima Tomohiko、Kanemaru Yosuke、Tateishi Hiroshi、Okamoto Yoshinari、Inoue Jun-ichiro、Fujita Mikako、Otsuka Masami
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 29 Issue: 16 Pages: 2162-2167
  • DOI: 10.1016/j.bmcl.2019.06.050
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 人工イノシトールリン脂質誘導体を用いた新規HIV-1根絶法の開発 (2019)
  • Author(s): 立石大
  • Organizer: 日本ケミカルバイオロジー学会 第14回年会
• [Presentation] IP6によるHIV制御メカニズムの解明とその誘導体L-HIPPOを用いたHIV根治薬の開発 (2019)
  • Author(s): 立石大
  • Organizer: 第42回 日本分子生物学会年会