INHIBITION OF HIV-1 INFECTIVITY BY ZINC-EJECTING AROMATIC C-NITROSO COMPOUNDS

RETROVIRAL nucleocapsid and gag-precursor proteins from all known strains of retroviruses contain one or two copies of an invariant sequence, Cys-X2-Cys-X4-His-X4-Cys1,2, that is populated with zinc in mature particles3. Modification of cysteine or histidine residues results in defective packaging of genomic viral RNA and formation of non-infectious particles4-8, making these structures potentially attractive targets for antiviral therapy3,8. We recently reported that aromatic C-nitroso ligands of poly(ADP-ribose) polymerase preferentially destabilize one of the two (CYS-X2-CYS-X28-His-X2-Cys) zinc-fingers with concomitant loss of enzymatic activity9,10, coincidental with selective cytocidal action of the C-nitroso substituted ligands on cancer cells11. Based on the occurrence of (3Cys, 1His) zinc-binding sites in both retroviral nucleocapsid and gag proteins and in poly(ADP-ribose) polymerase12, we reasoned that the C-nitroso compounds may also have antiretroviral effects. We show here that two such compounds, 3-nitrosobenzamide and 6-nitroso-1,2-benzopyrone, inhibit infection of human immunodeficiency virus HIV-1 in human lymphocytes and also eject zinc from isolated HIV-1 nucleocapsid zinc fingers and from intact HIV-1 virions. Thus the design of zinc-ejecting agents that target retroviral zinc fingers represents a new approach to the chemotherapy of AIDS.