2. Academic Validation
  3. Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

  • Antimicrob Agents Chemother. 2016 Mar 25;60(4):2195-208. doi: 10.1128/AAC.02574-15.
Suzie Thenin-Houssier 1,  Ian Mitchelle S de Vera 2,  Laura Pedro-Rosa 3,  Angela Brady 1,  Audrey Richard 1,  Briana Konnick 1,  Silvana Opp 4,  Cindy Buffone 4,  Jakob Fuhrmann 2,  Smitha Kota 5,  Blase Billack 6,  Magdalena Pietka-Ottlik 7,  Timothy Tellinghuisen 1,  Hyeryun Choe 1,  Timothy Spicer 3,  Louis Scampavia 3,  Felipe Diaz-Griffero 4,  Douglas J Kojetin 2,  Susana T Valente 8
Affiliations

Affiliations

  • 1 Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA.
  • 2 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
  • 3 Department of Molecular Therapeutics, Molecular Screening Center, The Scripps Research Institute, Jupiter, Florida, USA.
  • 4 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
  • 5 Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
  • 6 Department of Pharmaceutical Sciences, St. John's University, Jamaica, New York, USA.
  • 7 Department of Organic and Pharmaceutical Technology, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
  • 8 Department of Immunology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA svalente@scripps.edu.
PMID: 26810656 DOI: 10.1128/AAC.02574-15
Abstract

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 1,280in vivo-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.

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