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

Thomas Vercruysse,Yves Mély,François Debaene,Nicolas Humbert,Sarah Sanglier-Cianférani,Beata Basta,Wim Dehaen,Dirk Daelemans,Christophe Pannecouque,Jan Balzarini

doi:10.1186/1742-4690-9-95

Abstract

BackgroundSexual 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.ResultsHere, 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.ConclusionThis 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.

Highlights

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
WDO-217 was active against Human immunodeficiency virus type 1 (HIV-1) (IIIB) (EC50: 5 ± 3 μM), HIV-2 (ROD) (EC50: 2.3 ± 0.3 μM), and SIV (Mac251) (EC50: 5 ± 1 μM), Figure 1 Chemical structure of WDO-217
To assess the potential of WDO-217 against drugresistant HIV-1 strains, its antiviral activity was examined against virus strains that are resistant to either the entry inhibitor dextran sulfate, the CXCR4 antagonist AMD3100, the NRTI AZT, or the NNRTI nevirapine

Summary

Introduction

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. A number of classes of compounds targeting the retroviral NCp7 have been described, including, 3-nitrosobenzamide (NOBA) [7], 2,20-dithiobisbenzamides (DIBA) [8], cyclic 2,20dithiobisbenzamides (e.g. SRR-SB3) [9], 1,2-dithiane-4,5diol-1,1-dioxide [10], azadicarbonamide (ADA) [11,12], pyridinioalkanoyl thiolesters (PATEs) [13], bis-thiadiazolbenzene-1,2-diamines [14] and S-acyl-2-mercaptobenzamide thioesters (SAMTs) [15]. The latter class of compounds was recently considered for testing as topical microbicide for the prevention of HIV transmission [16]. WDO-217 qualifies as a potential microbicide lead compound for further (pre)clinical studies

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Results

Conclusion