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- Suzie Thenin-Houssier
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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- Ian Mitchelle S. de Vera
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA
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- Laura Pedro-Rosa
- Department of Molecular Therapeutics, Molecular Screening Center, The Scripps Research Institute, Jupiter, Florida, USA
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- Angela Brady
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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- Audrey Richard
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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- Briana Konnick
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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- Silvana Opp
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
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- Cindy Buffone
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
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- Jakob Fuhrmann
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA
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- Smitha Kota
- Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA
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- Blase Billack
- Department of Pharmaceutical Sciences, St. John's University, Jamaica, New York, USA
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- Magdalena Pietka-Ottlik
- Department of Organic and Pharmaceutical Technology, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland
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- Timothy Tellinghuisen
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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- Hyeryun Choe
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
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- Timothy Spicer
- Department of Molecular Therapeutics, Molecular Screening Center, The Scripps Research Institute, Jupiter, Florida, USA
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- Louis Scampavia
- Department of Molecular Therapeutics, Molecular Screening Center, The Scripps Research Institute, Jupiter, Florida, USA
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- Felipe Diaz-Griffero
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
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- Douglas J. Kojetin
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA
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- Susana T. Valente
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA
説明
<jats:title>ABSTRACT</jats:title> <jats:p> The human immunodeficiency virus type 1 (HIV-1) capsid plays crucial roles in HIV-1 replication and thus represents an excellent drug target. We developed a high-throughput screening method based on a time-resolved fluorescence resonance energy transfer (HTS-TR-FRET) assay, using the C-terminal domain (CTD) of HIV-1 capsid to identify inhibitors of capsid dimerization. This assay was used to screen a library of pharmacologically active compounds, composed of 1,280 <jats:italic>in vivo</jats:italic> -active drugs, and identified ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], an organoselenium compound, as an inhibitor of HIV-1 capsid CTD dimerization. Nuclear magnetic resonance (NMR) spectroscopic analysis confirmed the direct interaction of ebselen with the HIV-1 capsid CTD and dimer dissociation when ebselen is in 2-fold molar excess. Electrospray ionization mass spectrometry revealed that ebselen covalently binds the HIV-1 capsid CTD, likely via a selenylsulfide linkage with Cys198 and Cys218. This compound presents anti-HIV activity in single and multiple rounds of infection in permissive cell lines as well as in primary peripheral blood mononuclear cells. Ebselen inhibits early viral postentry events of the HIV-1 life cycle by impairing the incoming capsid uncoating process. This compound also blocks infection of other retroviruses, such as Moloney murine leukemia virus and simian immunodeficiency virus, but displays no inhibitory activity against hepatitis C and influenza viruses. This study reports the use of TR-FRET screening to successfully identify a novel capsid inhibitor, ebselen, validating HIV-1 capsid as a promising target for drug development. </jats:p>
収録刊行物
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- Antimicrobial Agents and Chemotherapy
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Antimicrobial Agents and Chemotherapy 60 (4), 2195-2208, 2016-04
American Society for Microbiology