Novel <i>bis</i> -Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro
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- Yasuhiro Koh
- Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
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- Hirotomo Nakata
- Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
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- Kenji Maeda
- Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
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- Hiromi Ogata
- Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
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- Geoffrey Bilcer
- Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607
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- Thippeswamy Devasamudram
- Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607
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- John F. Kincaid
- Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607
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- Peter Boross
- Department of Biology
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- Yuan-Fang Wang
- Department of Biology
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- Yunfeng Tie
- Department of Chemistry
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- Patra Volarath
- Department of Chemistry
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- Laquasha Gaddis
- Department of Biology
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- Robert W. Harrison
- Department of Biology
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- Irene T. Weber
- Department of Biology
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- Arun K. Ghosh
- Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607
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- Hiroaki Mitsuya
- Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan
抄録
<jats:title>ABSTRACT</jats:title> <jats:p> We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3( <jats:italic>R</jats:italic> ),3a( <jats:italic>S</jats:italic> ),6a( <jats:italic>R</jats:italic> )- <jats:italic>bis</jats:italic> -tetrahydrofuranylurethane ( <jats:italic>bis</jats:italic> -THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC <jats:sub>50</jats:sub> ], ∼0.003 μM; IC <jats:sub>90</jats:sub> , ∼0.009 μM) with minimal cytotoxicity (50% cytotoxic concentration for CD4 <jats:sup>+</jats:sup> MT-2 cells, 74 μM). UIC-94017 blocked the infectivity and replication of each of HIV-1 <jats:sub>NL4-3</jats:sub> variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 μM (IC <jats:sub>50</jats:sub> s, 0.003 to 0.029 μM), although it was less active against HIV-1 <jats:sub>NL4-3</jats:sub> variants selected for resistance to amprenavir (IC <jats:sub>50</jats:sub> , 0.22 μM). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections. </jats:p>
収録刊行物
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- Antimicrobial Agents and Chemotherapy
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Antimicrobial Agents and Chemotherapy 47 (10), 3123-3129, 2003-10
American Society for Microbiology
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詳細情報 詳細情報について
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- CRID
- 1363951796208817408
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- NII論文ID
- 30020631631
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- ISSN
- 10986596
- 00664804
- http://id.crossref.org/issn/00664804
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