The human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein zinc ejection activity of disulfide benzamides and benzisothiazolones: correlation with anti-HIV and virucidal activities.

AUTOR(ES)
RESUMO

It has been shown previously by our group and others that a series of four disulfide benzamides with cellular anti-human immunodeficiency virus (HIV) activity can eject zinc from HIV type 1 nucleocapsid protein (NCp7) in vitro while analogs without antiviral activity do not. We also found that the zinc ejection activity correlates with the loss of the ability of NCp7 to bind to HIV psi RNA in vitro. These observations indicate that the antiviral disulfide benzamides may act at a novel retroviral target of action, i.e., the nucleocapsid protein. The present studies examine the relationship among disulfide benzamide structure, in vitro NCp7 zinc ejection activity, and antiviral activity for a larger series of compounds. All of the antiviral disulfide benzamides were found to eject NCp7 zinc, while some disulfide benzamides with zinc ejection activity are not antiviral. Utilizing the thiol reagent 5,5'-dithiobis(2-nitrobenzoic acid), it was determined that the o-amido-phenyl disulfides being studied cyclize in aqueous solution to form benzisothiazolones. A series of benzisothiazolones, which are stable in solution in the absence of dithiothreitol, were found to eject NCp7 zinc at a rate similar to that of their disulfide benzamide analogs and to possess similar antiviral activity. It was also found that the relative rates of HIV inactivation by various disulfide benzamides and benzisothiazolones correlate with their relative kinetic rates of NCp7 zinc ejection, which is consistent with the nucleocapsid protein being the target of action of these compounds.

ACESSO AO ARTIGO

Documentos Relacionados