A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions
<p>Abstract</p> <p>Background</p> <p>Sexual acquisition of the human immunodeficiency virus (HIV) through mucosal transmission may be prevented by using topically applied agents that block HIV transmission from one individual to another. Therefore, virucidal agents that...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-11-01
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| Series: | Retrovirology |
| Subjects: | |
| Online Access: | http://www.retrovirology.com/content/9/1/95 |
| _version_ | 1811247664951459840 |
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| author | Vercruysse Thomas Basta Beata Dehaen Wim Humbert Nicolas Balzarini Jan Debaene François Sanglier-Cianférani Sarah Pannecouque Christophe Mély Yves Daelemans Dirk |
| author_facet | Vercruysse Thomas Basta Beata Dehaen Wim Humbert Nicolas Balzarini Jan Debaene François Sanglier-Cianférani Sarah Pannecouque Christophe Mély Yves Daelemans Dirk |
| author_sort | Vercruysse Thomas |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Sexual acquisition of the human immunodeficiency virus (HIV) through mucosal transmission may be prevented by using topically applied agents that block HIV transmission from one individual to another. Therefore, virucidal agents that inactivate HIV virions may be used as a component in topical microbicides.</p> <p>Results</p> <p>Here, we have identified 2-methyl-3-phenyl-2<it>H</it>-[1,2,4]thiadiazol-5-ylideneamine (WDO-217) as a low-molecular-weight molecule that inactivates HIV particles. Both HIV-1 and HIV-2 virions pretreated with this compound were unable to infect permissive cells. Moreover, WDO-217 was able to inhibit infections of a wide spectrum of wild-type and drug-resistant HIV-1, including clinical isolates, HIV-2 and SIV strains. Whereas the capture of virus by DC-SIGN was unaffected by the compound, it efficiently prevented the transmission of DC-SIGN-captured virus to CD4<sup>+</sup> T-lymphocytes. Interestingly, exposure of virions to WDO-217 reduced the amount of virion-associated genomic RNA as measured by real-time RT-qPCR. Further mechanism-of-action studies demonstrated that WDO-217 efficiently ejects zinc from the zinc fingers of the retroviral nucleocapsid protein NCp7 and inhibits the cTAR destabilization properties of this protein. Importantly, WDO-217 was able to eject zinc from both zinc fingers, even when NCp7 was bound to oligonucleotides, while no covalent interaction between NCp7 and WDO-217 could be observed.</p> <p>Conclusion</p> <p>This compound is a new lead structure that can be used for the development of a new series of NCp7 zinc ejectors as candidate topical microbicide agents.</p> |
| first_indexed | 2024-04-12T15:12:34Z |
| format | Article |
| id | doaj.art-f0eb9b40d71c4105a58b224f775eb844 |
| institution | Directory Open Access Journal |
| issn | 1742-4690 |
| language | English |
| last_indexed | 2024-04-12T15:12:34Z |
| publishDate | 2012-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Retrovirology |
| spelling | doaj.art-f0eb9b40d71c4105a58b224f775eb8442022-12-22T03:27:42ZengBMCRetrovirology1742-46902012-11-01919510.1186/1742-4690-9-95A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virionsVercruysse ThomasBasta BeataDehaen WimHumbert NicolasBalzarini JanDebaene FrançoisSanglier-Cianférani SarahPannecouque ChristopheMély YvesDaelemans Dirk<p>Abstract</p> <p>Background</p> <p>Sexual acquisition of the human immunodeficiency virus (HIV) through mucosal transmission may be prevented by using topically applied agents that block HIV transmission from one individual to another. Therefore, virucidal agents that inactivate HIV virions may be used as a component in topical microbicides.</p> <p>Results</p> <p>Here, we have identified 2-methyl-3-phenyl-2<it>H</it>-[1,2,4]thiadiazol-5-ylideneamine (WDO-217) as a low-molecular-weight molecule that inactivates HIV particles. Both HIV-1 and HIV-2 virions pretreated with this compound were unable to infect permissive cells. Moreover, WDO-217 was able to inhibit infections of a wide spectrum of wild-type and drug-resistant HIV-1, including clinical isolates, HIV-2 and SIV strains. Whereas the capture of virus by DC-SIGN was unaffected by the compound, it efficiently prevented the transmission of DC-SIGN-captured virus to CD4<sup>+</sup> T-lymphocytes. Interestingly, exposure of virions to WDO-217 reduced the amount of virion-associated genomic RNA as measured by real-time RT-qPCR. Further mechanism-of-action studies demonstrated that WDO-217 efficiently ejects zinc from the zinc fingers of the retroviral nucleocapsid protein NCp7 and inhibits the cTAR destabilization properties of this protein. Importantly, WDO-217 was able to eject zinc from both zinc fingers, even when NCp7 was bound to oligonucleotides, while no covalent interaction between NCp7 and WDO-217 could be observed.</p> <p>Conclusion</p> <p>This compound is a new lead structure that can be used for the development of a new series of NCp7 zinc ejectors as candidate topical microbicide agents.</p>http://www.retrovirology.com/content/9/1/95HIVNucleocapsidVirucideMicrobicide |
| spellingShingle | Vercruysse Thomas Basta Beata Dehaen Wim Humbert Nicolas Balzarini Jan Debaene François Sanglier-Cianférani Sarah Pannecouque Christophe Mély Yves Daelemans Dirk A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions Retrovirology HIV Nucleocapsid Virucide Microbicide |
| title | A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions |
| title_full | A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions |
| title_fullStr | A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions |
| title_full_unstemmed | A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions |
| title_short | A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions |
| title_sort | phenyl thiadiazolylidene amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates hiv virions |
| topic | HIV Nucleocapsid Virucide Microbicide |
| url | http://www.retrovirology.com/content/9/1/95 |
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