Development of Halogen-Containing Compounds Potent against Wild-type and Multidrug-Resistant HIV-1 Strains
Project/Area Number |
17H04222
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Infectious disease medicine
|
Research Institution | National Center for Global Health and Medicine |
Principal Investigator |
Hiroaki Mitsuya 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) |
2017-04-01 – 2020-03-31
|
Project Status |
Completed (Fiscal Year 2019)
|
Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
|
Keywords | HIV-1 / 阻害剤開発 / ハロゲン結合 |
Outline of Final Research Achievements |
In general, fluorination increases lipophilicity because the carbon-fluorine bond is more hydrophobic than the carbon-hydrogen bond, often enhancing cell membrane penetration and oral bioavailability of the compounds. Here, we newly designed and synthesized various novel PIs and attempted to determine proper fluorination sites in various moieties consisting of certain PIs. We found that various PIs acquire more potent anti-HIV-1 activity with proper fluorination. An existing challenge in development of novel PIs is that presently clinically available PIs are metabolized by cytochrome P450 enzymes and require co-administration of CYP inhibitors, causing annoying drug-drug interactions leading to adverse effects. We found that alkylamino modification at C5-position of tetrahydropyrano-tetrahydrofuran-containing PIs potentiates activity against multi-PI-resistant HIV-1 and the stability to CYP enzymes.
|
Academic Significance and Societal Importance of the Research Achievements |
本成果は、近年問題となっているHIV関連神経認知障害(HAND)の治療だけでなく、変遷しつつある抗レトロウイルス療法(Anti-retroviral therapy;ART)に対応した抗HIV薬開発の発展に資する。ARTの発展により感染者の余命が伸長しHANDが問題視されるようになった。中枢神経系透過性の高い2個のフッ素原子を有する新規化合物の開発に成功した。現在臨床試験が実施されているEFdAやカボテグラビルに代表されるようにARTは1日1回から1週間、1ヶ月に1回の投薬への変遷過程にある。今後は、ARTの発展と共に生じる新たな課題に応じた創薬開発が必要とされる。
|
Report
(4 results)
Research Products
(39 results)
-
-
-
-
-
-
[Journal Article] Novel Protease Inhibitors Containing C-5-Modified bis-Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance2019
Author(s)
Yuki Takamatsu, Manabu Aoki, Haydar Bulut, Debananda Das, Masayuki Amano, Venkata Reddy Sheri, Ladislau C. Kovari, Hironori Hayashi, Nicole S. Delino, Arun K. Ghosh, Hiroaki Mitsuya.
-
Journal Title
Antimicrobial Agents and Chemotherapy.
Volume: 63
Issue: 8
Pages: 1-1
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
[Journal Article] Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies.2019
Author(s)
Ghosh AK, Xia Z, Kovela S, Robinson WL, Johnson ME, Kneller DW, Wang YF, Aoki M, Takamatsu Y, Weber IT, Mitsuya H.
-
Journal Title
Chem Med Chem.
Volume: 14
Issue: 21
Pages: 1863-1872
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
[Journal Article] Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design, synthesis, and biological evaluation.2019
Author(s)
Ghosh AK, Williams JN, Kovela S, Takayama J, Simpson HM, Walters DE, Hattori SI, Aoki M, Mitsuya H.
-
Journal Title
Bioorg Med Chem Lett.
Volume: 29
Issue: 18
Pages: 2565-2570
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
-
[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
Related Report
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
Related Report
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
Related Report
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
Related Report
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
Related Report
Peer Reviewed / 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′ ligands2017
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
Related Report
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
DOI
Related Report
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
Related Report
Peer Reviewed / Int'l Joint Research
-
-
-
-
-
-
[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
Related Report
-
-
-
[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
Related Report
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
Related Report
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 HIVDRVRP512017
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
Related Report
-
-
[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 variants2017
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
Related Report
-
-
[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 variants2017
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18回熊本エイズセミナー
Related Report
-
[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 variants2017
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
Related Report
-