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: W G Rice, C A Schaeffer, B Harten, F Villinger, T L South, M F Summers, L E Henderson, J W Bess Jr, L O Arthur, J S McDougal
• Journal: Nature (Nature) Vol. 361 Issue 6411 Pg. 473-5 (Feb 04 1993) ISSN: 0028-0836 [Print] England
• PMID: 8429889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiviral Agents
• Benzamides
• Coumarins
• Gene Products, gag
• Nitroso Compounds
• 6-nitroso-1,2-benzopyrone
• Histidine
• 3-nitrosobenzamide
• Zinc
• Cysteine

Topics

• Amino Acid Sequence
• Antiviral Agents (pharmacology)
• Benzamides (pharmacology)
• Binding Sites
• Capsid (chemistry, drug effects, metabolism)
• Coumarins (pharmacology)
• Cysteine (chemistry)
• Gene Products, gag (chemistry, drug effects, metabolism)
• HIV-1 (drug effects, physiology)
• Histidine (chemistry)
• Humans
• Lymphocytes (microbiology)
• Magnetic Resonance Spectroscopy
• Molecular Sequence Data
• Nitroso Compounds (pharmacology)
• Zinc (metabolism)
• Zinc Fingers (drug effects)