Protease inhibitors exerting potent activity against wild type and multi-drug resistant HIV-1 variants without boosters.

• Project/Area Number: 17K19577
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pathology, Infection/Immunology, and related fields
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Mitsuya Hiroaki 国立研究開発法人国立国際医療研究センター, その他部局等, 研究所長 (20136724)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: ウイルス / HIV-1 / プロテアーゼ阻害剤 / CYP3A4 / 薬物動態

Outline of Final Research Achievements

We demonstrated that multiple novel PIs, which contain the tetrahydropyrano-tetrahydrofuran moiety (Tp-THF) with a C5-alkylamino group as a P2-ligand, displayed increased resistance to the metabolic activity of CYP enzymes. In particular, GRL-079-13A and GRL-015-16A, which contain P2-C5-alkylamino-modified Tp-THF and P2’-cyclopropyl-amino-benzothiazole (P2’-Cp-Abt), displayed increased CYP resistance as RTV and COBI did. We also determined the relationship between the chemical structures of PIs containing Tp-THF and the increase of intracellular TG amount in HepG2 cells. We found that P2’-Cp-Abt and P1-di-meta-fluorine modification increases intracellular TG levels but amine and methylamino modifications at the C5-position of Tp-THF do not affect adversely TG levels in HepG2 cells. These data would be useful to design novel PIs, which simplify the drug regimen by removing RTV or COBI from cART, thereby decreasing adverse effects in lipid metabolisms and drug-drug interactions.

Academic Significance and Societal Importance of the Research Achievements

ブースターを必要とせずQW又はQMでの投与で野生株及び多剤耐性HIV-1株の両方に高い阻害効果を発揮する抗 HIV-1剤を同定・開発するという本研究の試みはドラッグデザインの領域でも極めて先進的・挑戦的である。本研究で得られたCYP耐性と化合物の構造の相関関係はそのような新規抗HIV-1剤開発の基盤を成すものであり学術的・社会的意義は計り知れない。また、本研究成果は、ART の投薬方法の変革と感染患者のQOLの向上に必須であり、新たなHIV-1治療法の開拓に資する重要な成果である。

Research Products

• [Int'l Joint Research] NIH/Purdue University(米国)
• [Journal Article] GRL-079, a novel P2-Tp-THF-C5-alkylamine- and P2' -Abt-containing HIV-1 protease inhibitor, is extremely potent against multi-drug-resistant HIV-1 variants including HIVDRVRp51 and has a high genetic barrier against the emergence of resistant variants. (2018)
  • Author(s): Delino NS, Aoki M, Hayashi H, Hattori SI, Chang SB, Takamatsu Y, Martyr CD, Das D, Ghosh AK, Mitsuya H.
  • Journal Title: Antimicrob Agents Chemother. Volume: 62(5) Issue: 5 Pages: 02060-17
  • DOI: 10.1128/aac.02060-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants. (2018)
  • Author(s): Ghosh AK, Rao KV, Nyalapatla PR, Kovela S, Brindisi M, Osswald HL, Sekhara Reddy B, Agniswamy J, Wang YF, Aoki M, Hattori SI, Weber IT, Mitsuya H.
  • Journal Title: Chem Med Chem. Volume: 13(8) Issue: 8 Pages: 803-815
  • DOI: 10.1002/cmdc.201700824
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanism of Darunavir (DRV)'s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance. (2018)
  • Author(s): Aoki M, Das D, Hayashi H, Aoki-Ogata H, Takamatsu Y, Ghosh AK, Mitsuya H.
  • Journal Title: MBio. Volume: 9(2) Issue: 2
  • DOI: 10.1128/mbio.02425-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands. (2018)
  • Author(s): Ghosh AK, Jadhav RD, Simpson H, Kovela S, Osswald H, Agniswamy J, Wang YF, Hattori SI, Weber IT, Mitsuya H.
  • Journal Title: Eur J Med Chem. Volume: 160 Pages: 171-182
  • DOI: 10.1016/j.ejmech.2018.09.046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies. (2018)
  • Author(s): Ghosh AK, Williams JN, Ho RY, Simpson HM, Hattori SI, Hayashi H, Agniswamy J, Wang YF, Weber IT, Mitsuya H.
  • Journal Title: J Med Chem. Volume: 61(21) Issue: 21 Pages: 9722-9737
  • DOI: 10.1021/acs.jmedchem.8b01227
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir. (2018)
  • Author(s): Yasutake Y, Hattori SI, Hayashi H, Matsuda K, Tamura N, Kohgo S, Maeda K, Mitsuya H.
  • Journal Title: Sci Rep. Volume: 8(1) Issue: 1 Pages: 1624-1624
  • DOI: 10.1038/s41598-018-19602-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. (2017)
  • Author(s): Ghosh AK, Rao KV, Nyalapatla PR, Osswald HL, Martyr CD, Aoki M, Hayashi H, Agniswamy J, Wang YF, Bulut H, Das D, Weber IT, Mitsuya H.
  • Journal Title: J Med Chem. Volume: 60(10) Issue: 10 Pages: 4267-4278
  • DOI: 10.1021/acs.jmedchem.7b00172
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. (2017)
  • Author(s): Arun K. Ghosh , Margherita Brindisi, Prasanth R. Nyalapatla, Jun Takayama, Jean-Rene Ella-Menye, Sofiya Yashchuk, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 25 Issue: 19 Pages: 5114-5127
  • DOI: 10.1016/j.bmc.2017.04.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro. (2017)
  • Author(s): Masayuki Amano, Pedro Miguel Salcedo-Gomez, Ravikiran S. Yedidi, Nicole S. Delino, Hirotomo Nakata, Kalapala Venkateswara Rao, Arun K. Ghosh, Hiroaki Mitsuya.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12235-12235
  • DOI: 10.1038/s41598-017-12052-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1′-P2′ ligands (2017)
  • Author(s): Arun K. Ghosh, W. Sean Fyvie, Margherita Brindisi, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 27 Issue: 21 Pages: 4925-4931
  • DOI: 10.1016/j.bmcl.2017.09.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency. (2017)
  • Author(s): Aoki M, Hayashi H, Rao KV, Das D, Higashi-Kuwata N, Bulut H, Aoki-Ogata H, Takamatsu Y, Yedidi RS, Davis DA, Hattori SI, Nishida N, Hasegawa K, Takamune N, Nyalapatla PR, Osswald HL, Jono H, Saito H, Yarchoan R, Misumi S, Ghosh AK, Mitsuya H.
  • Journal Title: Elife Volume: 6
  • DOI: 10.7554/elife.28020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design, synthesis, biological evaluation, and X-ray studies of HIV-1 protease inhibitors with modified P2'-ligands of Darunavir. (2017)
  • Author(s): Arun K Ghosh, W. Sean Fyvie, Margherita Brindisi, Melinda Steffey, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Masayuki Amano, Irene T. Weber, Hiroaki Mitsuya.
  • Journal Title: ChemMedChem Volume: 12 Issue: 23 Pages: 1942-1952
  • DOI: 10.1002/cmdc.201700614
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 多剤耐性HIV変異株にも強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤の同定とその機序 (2018)
  • Author(s): 服部真一朗、林宏典、Haydar Bult、青木学、長谷川和也、Arun K. Ghosh、満屋裕明
  • Organizer: 第28回抗ウイルス療法学会学術集会・総会
• [Presentation] 極めて強力な活性を有する新規HIV-1プロテアーゼ阻害剤GRL-142 /KU-241の同定及びその SIVmac251感染サルにおける抗SIV効果の検討 (2018)
  • Author(s): 鍬田伸好, 青木学, Viraj Kulkarni, 服部真一朗, 青木宏美, 林宏典, 城野博史, 山川佑可子, 前田賢次, 刈谷龍昇, 岡田誠治, Arun K. Ghosh, Ruth M. Ruprecht, 満屋裕明
  • Organizer: 第20回白馬シンポジウム in 屋久島
• [Presentation] 多剤耐性HIV変異株にも強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤の同定とその活性・構造相関 (2018)
  • Author(s): 服部真一朗、林宏典、Haydar Bulut、Debananda Das、長谷川和也、青木学、Arun K. Ghosh、満屋裕明
  • Organizer: 第20回白馬シンポジウム in 屋久島
• [Presentation] 極めて強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤の同定とその機序 (2018)
  • Author(s): 服部真一朗、林宏典、Bulut Haydar、長谷川和也、青木学、Ghosh Arun K.、満屋裕明
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] Discovery of an unprecedentedly potent HIV-1 protease inhibitor, GRL-0142, and its biological features. (2018)
  • Author(s): Manabu Aoki, Nobuyo Higashi-Kuwata, Hiromi Aoki, Haydar Bulut, Debananda Das, Ruth M. Ruprecht, Arun K. Ghosh, Hiroaki Mitsuya
  • Organizer: HIV DART & EMERGING VIRUSES
  • Int'l Joint Research
• [Presentation] A novel HIV protease inhibitor, GRL-142, binds to interase and potently blocks INSTI-resistant HIV-1 varients (2018)
  • Author(s): Manabu Aoki, Hydar Bulut, Yuki Takamatsu, Tomofumi Nakamura, Arun Ghosh, Hiroaki Mitsuya
  • Organizer: HIV DART & EMERGING VIRUSES
  • Int'l Joint Research
• [Presentation] Antiviral activity of GRL-142 against SIVmac251 in Rhesus macaques. (2018)
  • Author(s): Nobuyo Kuwata, Manabu Aoki, Viraj Kulkarni, Shin-ichiro Hattori, Hiromi Aoki, Ryusho Kariya, Hirofumi Jono, Yukako Yamakawa, Seiji Okada, Arun Ghosh, Ruth Ruprecht, Hiroaki Mitsuya
  • Organizer: HIV DART & EMERGING VIRUSES
  • Int'l Joint Research
• [Presentation] P2-Tp-THF-C5-alkylamine and P'2-Abt contribute to the potency of newly-generated protease inhibitors against a wide spectrum of HIVMDRS including HIVDRVRP51 (2017)
  • Author(s): Nicole S. Delino, Manabu Aoki, Hironori Hayashi, Haydar Bulut, Shin-ichiro Hattori, Simon B. Chang, Yuki Takamatsu, Cuthbert D. Martyr, Debananda Das, Arun K. Ghosh, and Hiroaki Mitsuya,
  • Organizer: 第27回抗ウイルス療法学会学術集会・総会
• [Presentation] P1-phenylにフッ素原子を導入したHIVプロテアーゼ阻害剤は強力な抗ウイルス活性を発揮する (2017)
  • Author(s): 服部真一朗、林宏典、青木学、Debananda Das、青木宏美、鍬田伸好、高松悠樹、Yedidi Ravikran、長谷川和也、Arun K Ghosh、前田賢次、満屋裕明
  • Organizer: 第27回抗ウイルス療法学会学術集会・総会
• [Presentation] GRL-079, a novel P2-Tp-THF-C5-alkylamine- and P2’-Abt-containing HIV-1 protease inhibitor, is extremely potent against a wide spectrum of HIVMDRs including HIVDRVRp51 with a high genetic barrier against the emergence of resistant variants, (2017)
  • Author(s): Nicole S. Delino, Manabu Aoki, Hironori Hayashi, Shin-ichiro Hattori, Simon B. Chang, Yuki Takamatsu, Cuthbert D. Martyr, Debananda Das, Arun K. Ghosh, and Hiroaki Mitsuya,
  • Organizer: 第19回白馬シンポジウムin仙台
• [Presentation] 多剤耐性HIV変異株に対して強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤、GRL-001～004の同定と構造・活性相関 (2017)
  • Author(s): 服部真一朗、林宏典、青木学、長谷川和也、青木宏美、鍬田伸好、Haydar Bulut、Debananda Das、前田賢次、Arun K. Ghosh、満屋裕明
  • Organizer: 第19回白馬シンポジウムin仙台
• [Presentation] GRL-079, a novel P2-Tp-THF-C5-alkylamine- and P2’-Abt-containing HIV-1 protease inhibitor, is extremely potent against a wide spectrum of multi-drug-resistant HIVs including HIVDRVRp51 and has a high genetic barrier against the emergence of resistant variants (2017)
  • Author(s): Nicole S. Delino, Manabu Aoki, Hironori Hayashi, Shin-ichiro Hattori, Simon B. Chang, Yuki Takamatsu, Cuthbert D. Martyr, Debananda Das, Arun K. Ghosh, and Hiroaki Mitsuy
  • Organizer: 第18回熊本エイズセミナー
• [Presentation] GRL-079, a novel P2-Tp-THF-C5 alkylamine and P2’-Abt-containing HIV-1 protease inhibitor, is extremely potent against a wide spectrum of HIVMDRs, including HIVDRVRp51, with a high genetic barrier against the emergence of resistant variants. (2017)
  • Author(s): Nicole S. Delino, Aoki Manabu, Hayashi Hironori,Hattori Shin-ichiro, Simon B. Chang, Takamatsu Yuki, Cuthbert D. Martyr, Debananda Das, Arun K. Ghosh, and Mitsuya Hiroaki,
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] 多剤耐性HIV変異株にも強力な抗ウイルス活性を発揮する新規HIVプロテアーゼ阻害剤の同定 (2017)
  • Author(s): 服部真一朗、林宏典、青木学、長谷川和也、Haydar Bulut、Debananda Das、Arun Ghosh、満屋裕明,
  • Organizer: 第31回日本エイズ学会学術集会・総会