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Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds

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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-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, 1 His) 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-l,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.

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Authors and Affiliations

  1. Laboratory of Antiviral Drug Mechanisms, Program Resources Inc./DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland, 21702, USA

    William G. Rice, Catherine A. Schaeffer & Brad Harten

  2. AIDS Vaccine Program, Program Resources Inc./DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland, 21702, USA

    Louis E. Henderson, Julian W. Bess Jr & Larry O. Arthur

  3. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Francois Villinger

  4. Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, Maryland, 21228, USA

    Terri L. South & Michael F. Summers

  5. Immunology Branch, DMA, NCID, Centers for Disease Control,US Public Health Service, Atlanta, Georgia, 30333, USA

    J. Steven McDougal & Sherry L. Orloff

  6. Octamer Inc., and the Laboratory for Environmental Toxicology and Chemistry, The Romberg Tiburon Centers, San Francisco State University, PO Box 855, Tiburon, California, 94920, USA

    Jerome Mendeleyev & Ernest Kun

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  1. William G. Rice
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  7. Louis E. Henderson
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  8. Julian W. Bess Jr
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  9. Larry O. Arthur
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  10. J. Steven McDougal
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  12. Jerome Mendeleyev
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  13. Ernest Kun
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Rice, W., Schaeffer, C., Harten, B. et al. Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds. Nature 361, 473–475 (1993). https://doi.org/10.1038/361473a0

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  • DOI: https://doi.org/10.1038/361473a0

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