Development of Novel HIV-1 Protease Dimerization Inhibitors Using Crystal Structure, Thermal Stability and Mass Spectrum Analyses

• Project/Area Number: 15K15382
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: Mitsuya Hiroaki 熊本大学, 大学院生命科学研究部, 教授 (20136724)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: AIDS/HIV-1 / 二量体化阻害剤 / 結晶構造解析 / 熱安定性 / 質量分析 / HIV-1 / 新規抗HIV-1剤開発 / 二量体化阻害

Outline of Final Research Achievements

The purpose of this project was the development of novel HIV-1 protease dimerization inhibitors (PDIs), which were potent against both wild type HIV-1 (HIV-1WT) and multiple drug-resistant HIV-1 variants (HIV-1MDRs). During the study period, we obtained two important results. (i) Using the crystal structural analysis, we identified key functional groups of novel protease inhibitors (GRL-015, -085, and -097). The functional groups in such protease inhibitors interacted with the flap region of HIV-1 protease and enabled such novel inhibitors to block the replication of HIV-1MDRs. (ii) Using electrospray ionization mass spectrometer (ESI-MS), we demonstrated the mechanisms of the most potent PDI termed as KU-241. KU-241 inhibited PR dimerization by binding PR monomer in the same way as darunavir, which was approved by FDA in 2006. The present results should shed light on designing further novel PDIs, which would inhibit both HIV-1WT and HIV-1MDRs.

Research Products

• [Journal Article] C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir (2015)
  • Author(s): Aoki, M. Hayashi, H. Yedidi, R. S. Martyr, C. D. Takamatsu, Y. Aoki-Ogata, H. Nakamura, T. Nakata, H. Das, D. Yamagata, Y. Ghosh, A. K. Mitsuya, H.
  • Journal Title: Journal of Virology Volume: 90 Issue: 5 Pages: 2180-94
  • DOI: 10.1128/jvi.01829-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Studies. (2015)
  • Author(s): Ghosh, AK., Martyr, CD., Osswald, HL., Sheri, VR., Kassekert, LA., Chen, S., Agniswamy, J., Wang, YF., Hayashi, H., Aoki, M., Weber, IT., and Mitsuya, H.
  • Journal Title: J Med Chem Volume: 58 Issue: 17 Pages: 6994-7006
  • DOI: 10.1021/acs.jmedchem.5b00900
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A NOVEL TRICYCLIC LIGAND-CONTAINING NONPEPTIDIC HIV-1 PROTEASE INHIBITOR, GRL-0739, EFFECTIVELY INHIBITS THE REPLICATION OF MULTI-DRUG-RESISTANT HIV-1 VARIANTS AND HAS A DESIRABLE CENTRAL NERVOUS SYSTEM (CNS) PENETRATION PROPERTY IN VITRO (2015)
  • Author(s): Masayuki Amano, Yasushi Tojo, Pedro Miguel Salcedo-Gómez, Garth L. Parham, Prasanth R. Nyalapatla, Debananda Das, Arun K. Ghosh and Hiroaki Mitsuya
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 59 Issue: 5 Pages: 2625-2635
  • DOI: 10.1128/aac.04757-14
  • Peer Reviewed / Open Access
• [Journal Article] Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands. (2015)
  • Author(s): Arun K. Ghosh, Jun Takayama, Luke A. Kassekert, Jean-Rene Ella-Menye, Sofiya Yashchuk, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: Bioorg Med Chem Lett. Volume: 25 Issue: 21 Pages: 4903-4909
  • DOI: 10.1016/j.bmcl.2015.05.052
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation. (2015)
  • Author(s): Arun K. Ghosh, Sofiya Yashchuk, Akira Mizuno, Nilanjana Chakraborty, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Pedro Miguel Salcedo Gomez, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: ChemMedChem Volume: 10 Issue: 1 Pages: 107-115
  • DOI: 10.1002/cmdc.201402358
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Novel protease inhibitors, which bind to protease’s flap region, strongly inhibit multi-drug resistant HIV-1 variants including darunavir-resistant variants (2015)
  • Author(s): Hironori Hayashi、Manabu Aoki、Ravikiran S. Yedidi、Hirotomo Nakata、Debananda Das、Teruya NakamuraKazuya Hasegawa、Yuriko Yamagata、Arun K. Ghosh、Hiroaki Mitsuya
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京ドームホテル（東京都）
  • Year and Date: 2015-11-30
• [Presentation] n vitro evaluation of the genotoxic potential of the novel anti-HIV protease inhibitor, KU-241, which is potent against multi-PI-Resistant HIV-1 variants (2015)
  • Author(s): Nobuyo Higashi-Kuwata、Manabu Aoki1、Shinichiro Hattori、Hiromi Ogata-Aoki、Hironori Hayashi、Kenji Maeda、Arun K. Ghosh、Hiroaki Mitsuya
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京ドームホテル（東京都）
  • Year and Date: 2015-11-30
• [Presentation] 新規HIV-1 プロテアーゼ阻害剤KU-241 の同定と抗HIV 活性の検討 (2015)
  • Author(s): 服部 真一朗、青木 学、鍬田 伸好、青木 宏美、林 宏典、Arun K. Ghosh、前田 賢次、満屋 裕明
  • Organizer: 第29回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京ドームホテル（東京都）
  • Year and Date: 2015-11-30
• [Presentation] Novel protease inhibitors, which bind to the flap region of HIV-1 protease, strongly inhibit multi-drug resistant HIV-1 variants including darunavir- resistant variants. (2015)
  • Author(s): Hironori Hayashi, Manabu Aoki, Ravikiran S. Yedidi, Hirotomo Nakata, Debananda Das, Teruya Nakamura, Kazuya Hasegawa, Yuriko Yamagata, Arun K. Ghosh and Hiroaki Mitsuya
  • Organizer: 第16回熊本エイズセミナー
  • Place of Presentation: 阿蘇ホテルグランビリオ（熊本県阿蘇市）
  • Year and Date: 2015-10-07
• [Presentation] Modified P1-Moiety Enhances Antiviral Activity against Drug-Resistant HIV-1 Variants and Central Nervous System (CNS) Penetration Effectiveness of Newly-Generated HIV-1 Protease Inhibitors In Vitro. (2015)
  • Author(s): Masayuki Amano and Hiroaki Mitsuya
  • Organizer: 第16回熊本エイズセミナー
  • Place of Presentation: 阿蘇ホテルグランビリオ（熊本県阿蘇市）
  • Year and Date: 2015-10-07
• [Presentation] 新規HIV-1プロテアーゼ阻害剤開発と構造解析 (2015)
  • Author(s): 林 宏典、青木 学、Yedidi Ravikiran、中田 浩智、Debananda Das、中村 照也、長谷川 和也、山縣 ゆり子、Arun K Ghosh、満屋 裕明
  • Organizer: 第17回白馬シンポジウム
  • Place of Presentation: 鳥取大学医学部（鳥取県米子市）
  • Year and Date: 2015-06-19