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

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 4; pp. 2195 - 2208
• Main Authors: Thenin-Houssier, Suzie, de Vera, Ian Mitchelle S, Pedro-Rosa, Laura, Brady, Angela, Richard, Audrey, Konnick, Briana, Opp, Silvana, Buffone, Cindy, Fuhrmann, Jakob, Kota, Smitha, Billack, Blase, Pietka-Ottlik, Magdalena, Tellinghuisen, Timothy, Choe, Hyeryun, Spicer, Timothy, Scampavia, Louis, Diaz-Griffero, Felipe, Kojetin, Douglas J, Valente, Susana T
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-04-2016
• Subjects: Anti-HIV Agents; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antiviral Agents; Azoles; Azoles - chemistry; Azoles - pharmacology; Binding Sites; Capsid; Capsid - chemistry; Capsid - drug effects; Capsid - metabolism; Capsid Proteins; Capsid Proteins - antagonists & inhibitors; Capsid Proteins - chemistry; Capsid Proteins - metabolism; Databases, Pharmaceutical; Fluorescence Resonance Energy Transfer; HeLa Cells; High-Throughput Screening Assays; HIV-1; HIV-1 - drug effects; HIV-1 - physiology; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - virology; Life Sciences; Moloney murine leukemia virus - drug effects; Moloney murine leukemia virus - physiology; Organoselenium Compounds; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Protein Binding; Protein Domains; Protein Multimerization - drug effects; Protein Structure, Secondary; Simian Immunodeficiency Virus - drug effects; Simian Immunodeficiency Virus - physiology; Small Molecule Libraries; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Virus Assembly - drug effects; Virus Assembly - physiology; Virus Replication - drug effects; HIV-1; capsid inhibitor
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.02574-15

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.