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

It has been shown previously by our group and others that a series of four disulfide benzamides with cellular anti-human immunodeficiency vi rus (HIV) activity can eject zinc from HIV type 1 nucleocapsid protein (NCp7) in vitro while analogs without antiviral activity do not. We a lso found that the zinc ejection activity correlates with the loss of the ability of NCp7 to bind to HIV Psi RNA in vitro. These observation s indicate that the antiviral disulfide benzamides may act at a novel retroviral target of action, i.e., the nucleocapsid protein. The prese nt studies examine the relationship among disulfide benzamide structur e, 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 zi nc 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 be nzisothiazolones. A series of benzisothiazolones, which are stable in solution in the absence of dithiothreitol, mere found to eject NCp7 zi nc at a rate similar to that of their disulfide benzamide analogs and to possess similar antiviral activity. It was also found that the rela tive rates of HIV inactivation by various disulfide benzamides and ben zisothiazolones correlate with their relative kinetic rates of NCp7 zi nc ejection, which is consistent with the nucleocapsid protein being t he target of action of these compounds.