ZINC EJECTION AS A NEW RATIONALE FOR THE USE OF CYSTAMINE AND RELATEDDISULFIDE-CONTAINING ANTIVIRAL AGENTS IN THE TREATMENT OF AIDS

The highly conserved and mutationally intolerant retroviral zinc finge r motif of the HIV-1 nucleocapsid protein (NC) is an attractive target for drug therapy due to its participation in multiple stages of the v iral replication cycle. A literature search identified cystamine, thia mine disulfide, and disulfiram as compounds that have been shown to in hibit HIV-1 replication by poorly defined mechanisms and that have ele ctrophilic functional groups that might react with the metal-coordinat ing sulfur atoms of the retroviral zinc fingers and cause zinc ejectio n. H-1 NMR studies reveal that these compounds readily eject zinc from synthetic peptides with sequences corresponding to the HIV-1 NC zinc fingers, as well as from the intact HIV-1 NC protein. In contrast, the reduced forms of disulfiram and cystamine, diethyl dithiocarbamate an d cysteamine, respectively, were found to be ineffective at zinc eject ion, although cysteamine formed a transient complex with the zinc fing ers. Studies with HIV-l-infected human T-cells and monocyte/macrophage cultures revealed that cystamine and cysteamine possess significant a ntiviral properties at nontoxic concentrations, which warrant their co nsideration as therapeutically useful anti-HIV agents.