Title: Development of an alphascreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors
Authors: Demeulemeester, Jonas
Tintori, Cristina
Botta, Maurizio
Debyser, Zeger
Christ, Frauke # ×
Issue Date: 14-Jun-2012
Publisher: Mary Ann Liebert
Series Title: Journal of Biomolecular Screening vol:17 issue:5 pages:618-628
Abstract: In recent years, HIV-1 integrase (IN) has become an established target in the field of antiretroviral drug discovery. However, its sole clinically approved inhibitor, the integrase strand transfer inhibitor (INSTI) raltegravir, has a surprisingly low genetic barrier for resistance. Furthermore, the only two other integrase inhibitors currently in advanced clinical trials, elvitegravir and dolutegravir, share its mechanism of action and certain resistance pathways. To maintain a range of treatment options, drug discovery efforts are now turning toward allosteric IN inhibitors, which should be devoid of cross-resistance with INSTIs. As IN requires a precise and dynamic equilibrium between several oligomeric species for its activities, the modulation of this equilibrium presents an interesting allosteric target. We report on the development, characterization, and validation of an AlphaScreen-based assay for high-throughput screening for modulators of HIV-1 IN dimerization. Compounds identified as hits in this assay proved to act as allosteric IN inhibitors. Additionally, the assay offers a flexible platform to study IN dimerization.
ISSN: 1087-0571
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
× corresponding author
# (joint) last author

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