Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import
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, continue...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | Retrovirology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12977-018-0389-2 |
| _version_ | 1818268906541809664 |
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| author | Jonas Demeulemeester Jolien Blokken Stéphanie De Houwer Lieve Dirix Hugo Klaassen Arnaud Marchand Patrick Chaltin Frauke Christ Zeger Debyser |
| author_facet | Jonas Demeulemeester Jolien Blokken Stéphanie De Houwer Lieve Dirix Hugo Klaassen Arnaud Marchand Patrick Chaltin Frauke Christ Zeger Debyser |
| author_sort | Jonas Demeulemeester |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T20:45:56Z |
| format | Article |
| id | doaj.art-63a93df1652e401dbed0fe23725e89f6 |
| institution | Directory Open Access Journal |
| issn | 1742-4690 |
| language | English |
| last_indexed | 2024-12-12T20:45:56Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Retrovirology |
| spelling | doaj.art-63a93df1652e401dbed0fe23725e89f62022-12-22T00:12:35ZengBMCRetrovirology1742-46902018-01-0115111310.1186/s12977-018-0389-2Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear importJonas Demeulemeester0Jolien Blokken1Stéphanie De Houwer2Lieve Dirix3Hugo Klaassen4Arnaud Marchand5Patrick Chaltin6Frauke Christ7Zeger Debyser8Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU LeuvenLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU LeuvenLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU LeuvenLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU LeuvenCenter for Innovation and Stimulation of Drug Discovery (CISTIM)Center for Innovation and Stimulation of Drug Discovery (CISTIM)Center for Innovation and Stimulation of Drug Discovery (CISTIM)Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU LeuvenLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU LeuvenAbstract 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.http://link.springer.com/article/10.1186/s12977-018-0389-2Drug discoveryIntegraseTransportin-SR2HIVNuclear import |
| spellingShingle | Jonas Demeulemeester Jolien Blokken Stéphanie De Houwer Lieve Dirix Hugo Klaassen Arnaud Marchand Patrick Chaltin Frauke Christ Zeger Debyser Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import Retrovirology Drug discovery Integrase Transportin-SR2 HIV Nuclear import |
| title | Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import |
| title_full | Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import |
| title_fullStr | Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import |
| title_full_unstemmed | Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import |
| title_short | Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import |
| title_sort | inhibitors of the integrase transportin sr2 interaction block hiv nuclear import |
| topic | Drug discovery Integrase Transportin-SR2 HIV Nuclear import |
| url | http://link.springer.com/article/10.1186/s12977-018-0389-2 |
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