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

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.

Advances in targeting nucleocapsid–nucleic acid interactions in HIV-1 therapy

“…Another relatively recently reported category of zinc ejectors are the thiadiazaole derivatives that act by zinc chelation (Fig 3) (Pannecouque et al, 2010; Vercruysse et al, 2012). Unlike the thioesters, thiadiazaole derivatives do not form covalent bonds with the NC protein.…”

“…Unlike the thioesters, thiadiazaole derivatives do not form covalent bonds with the NC protein. Treatment of infected cells with the phenyl-thiadiazolidene amine derivative does not result in accumulation of unprocessed Gag (Vercruysse et al, 2012). Therefore these molecules probably act at a different step in the viral life cycle than the thioesters.…”

Drug Resistance in Bacteria, Fungi, Malaria, and Cancer

“…There is still tremendous scope for targeting the clinically validated HIV targets (RT, IN, PR, and CCR5) through diverse mechanisms of action, such as RNase H inhibitors , nucleotide-competing RT inhibitors (NcRTIs) (Maga et al 2010), allosteric IN inhibitors, and PR dimerization inhibitors ). These targets include the dimerization initiation site (DIS) of the HIV-1 genomic RNA (Ennifar et al 2013), HIV-1 matrix protein (Zentner et al 2013), HIV-1 capsid (Dewan et al 2012), nuclear import of pre-integration complex (Zhan et al 2010), retroviral nucleocapsid zinc fingers (Vercruysse et al 2012), and many host antiviral restriction factors (Sloan and Wainberg 2013). These targets include the dimerization initiation site (DIS) of the HIV-1 genomic RNA (Ennifar et al 2013), HIV-1 matrix protein (Zentner et al 2013), HIV-1 capsid (Dewan et al 2012), nuclear import of pre-integration complex (Zhan et al 2010), retroviral nucleocapsid zinc fingers (Vercruysse et al 2012), and many host antiviral restriction factors (Sloan and Wainberg 2013).…”

Identification of anti-HIV agents with a novel benzo[4,5]isothiazolo[2,3-a]pyrimidine scaffold

“…Although there have been several reports that similar isothiazolidine and thiadiazole derivatives exhibited anti-HIV activities as zinc finger inhibitors for HIV-1 nucleocapsid protein 7 (NCp7), 22,23 this tetrahydropyrimidine-fused heterocyclic scaffold has not been explored as a potential anti-HIV agent candidate. In the current study, we investigated the synthesis of benzo [4,5]isothiazolo[2,3-a]pyrimidine derivatives and their structure-activity relationships as potent anti-HIV agents.…”