title: Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds.
abstract: 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-Cys, that is populated with zinc in mature particles. Modification of cysteine or histidine residues results in defective packaging of genomic viral RNA and formation of non-infectious particles, making these structures potentially attractive targets for antiviral therapy. 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 activity, coincidental with selective cytocidal action of the C-nitroso substituted ligands on cancer cells. Based on the occurrence of (3Cys, 1His) zinc-binding sites in both retroviral nucleocapsid and gag proteins and in poly(ADP-ribose) polymerase, 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 isoalted 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.
authors.affiliation: Laboratory of Antiviral Drug Mechanisms, Program Resources Inc./DynCorp., National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702.
authors.forename: W G
authors.initials: WG
authors.lastname: Rice
authors.forename: C A
authors.initials: CA
authors.lastname: Schaeffer
authors.forename: B
authors.initials: B
authors.lastname: Harten
authors.forename: F
authors.initials: F
authors.lastname: Villinger
authors.forename: T L
authors.initials: TL
authors.lastname: South
authors.forename: M F
authors.initials: MF
authors.lastname: Summers
authors.forename: L E
authors.initials: LE
authors.lastname: Henderson
authors.forename: J W
authors.initials: JW
authors.lastname: Bess
authors.forename: L O
authors.initials: LO
authors.lastname: Arthur
authors.forename: J S
authors.initials: JS
authors.lastname: McDougal
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry; D015683:Gene Products, gag / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008214:Lymphocytes / Q000382:microbiology; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009603:Nitroso Compounds / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D003374:Coumarins; D015683:Gene Products, gag; D009603:Nitroso Compounds; C071196:6-nitroso-1,2-benzopyrone; D006639:Histidine; C076039:3-nitrosobenzamide; D015032:Zinc; D003545:Cysteine