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Open Access Highly Accessed Research

A phenyl-thiadiazolylidene-amine derivative ejects zinc from retroviral nucleocapsid zinc fingers and inactivates HIV virions

Thomas Vercruysse1, Beata Basta2, Wim Dehaen3, Nicolas Humbert2, Jan Balzarini1, François Debaene45, Sarah Sanglier-Cianférani45, Christophe Pannecouque1, Yves Mély2* and Dirk Daelemans1*

Author Affiliations

1 Rega Institute for Medical Research, Laboratory for Virology and Chemotherapy, KU Leuven, Minderbroedersstraat 10, Leuven, B-3000, Belgium

2 Laboratoire de Biophotonique et Pharmacologie, UMR 7213 du CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, Illkirch, 67401, France

3 Chemistry Department, KU Leuven, Celestijnenlaan 200F, Leuven, B-3001, Belgium

4 Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, IPHC, 25 rue Becquerel, Strasbourg, 67087, France

5 CNRS, UMR7178, Strasbourg, 67037, France

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Retrovirology 2012, 9:95  doi:10.1186/1742-4690-9-95

Published: 12 November 2012

Abstract

Background

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.

Results

Here, we have identified 2-methyl-3-phenyl-2H-[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+ 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.

Conclusion

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.

Keywords:
HIV; Nucleocapsid; Virucide; Microbicide