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-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.
Rice
W G
WG
Laboratory of Antiviral Drug Mechanisms, Program Resources Inc./DynCorp., National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702.
Schaeffer
C A
CA
Harten
B
B
Villinger
F
F
South
T L
TL
Summers
M F
MF
Henderson
L E
LE
Bess
J W
JW
Arthur
L O
LO
McDougal
J S
JS
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*
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