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Retrovirology. 2018 Jan 12;15(1):5. doi: 10.1186/s12977-018-0389-2.

Inhibitors of the integrase-transportin-SR2 interaction block HIV nuclear import.

Author information

1
Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Kapucijnenvoer 33, VCTB +5, Bus 7001, 3000, Leuven, Flanders, Belgium.
2
The Francis Crick Institute, London, UK.
3
Center for Innovation and Stimulation of Drug Discovery (CISTIM), Leuven, Belgium.
4
Center for Drug Design and Development (CD3), KU Leuven R&D, Leuven, Belgium.
5
Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Kapucijnenvoer 33, VCTB +5, Bus 7001, 3000, Leuven, Flanders, Belgium. zeger.debyser@kuleuven.be.

Abstract

BACKGROUND:

Combination antiretroviral therapy efficiently suppresses HIV replication in infected patients, transforming HIV/AIDS into a chronic disease. Viral resistance does develop however, especially under suboptimal treatment conditions such as poor adherence. As a consequence, continued exploration of novel targets is paramount to identify novel antivirals that do not suffer from cross-resistance with existing drugs. One new promising class of targets are HIV protein-cofactor interactions. Transportin-SR2 (TRN-SR2) is a β-karyopherin that was recently identified as an HIV-1 cofactor. It has been implicated in nuclear import of the viral pre-integration complex and was confirmed as a direct binding partner of HIV-1 integrase (IN). Nevertheless, consensus on its mechanism of action is yet to be reached.

RESULTS:

Here we describe the development and use of an AlphaScreen-based high-throughput screening cascade for small molecule inhibitors of the HIV-1 IN-TRN-SR2 interaction. False positives and nonspecific protein-protein interaction inhibitors were eliminated through different counterscreens. We identified and confirmed 2 active compound series from an initial screen of 25,608 small molecules. These compounds significantly reduced nuclear import of fluorescently labeled HIV particles.

CONCLUSIONS:

Alphascreen-based high-throughput screening can allow the identification of compounds representing a novel class of HIV inhibitors. These results corroborate the role of the IN-TRN-SR2 interaction in nuclear import. These compounds represent the first in class small molecule inhibitors of HIV-1 nuclear import.

KEYWORDS:

Drug discovery; HIV; Integrase; Nuclear import; Transportin-SR2

PMID:
29329553
PMCID:
PMC5767004
DOI:
10.1186/s12977-018-0389-2
[Indexed for MEDLINE]
Free PMC Article

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