Title |
Inhibitors of the integrase–transportin-SR2 interaction block HIV nuclear import
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Published in |
Retrovirology, January 2018
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DOI | 10.1186/s12977-018-0389-2 |
Pubmed ID | |
Authors |
Jonas Demeulemeester, Jolien Blokken, Stéphanie De Houwer, Lieve Dirix, Hugo Klaassen, Arnaud Marchand, Patrick Chaltin, Frauke Christ, Zeger Debyser |
Abstract |
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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Belgium | 1 | 25% |
United Kingdom | 1 | 25% |
Unknown | 2 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 50% |
Scientists | 1 | 25% |
Science communicators (journalists, bloggers, editors) | 1 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 32 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 5 | 16% |
Researcher | 4 | 13% |
Student > Doctoral Student | 3 | 9% |
Student > Ph. D. Student | 3 | 9% |
Student > Master | 3 | 9% |
Other | 4 | 13% |
Unknown | 10 | 31% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 10 | 31% |
Arts and Humanities | 2 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 6% |
Psychology | 2 | 6% |
Agricultural and Biological Sciences | 1 | 3% |
Other | 4 | 13% |
Unknown | 11 | 34% |