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Azodicarbonamide Inhibits Hiv-1 Replication By Targeting the Nucleocapsid Protein

  1. Author:
    Rice, W. G.
    Turpin, J. A.
    Huang, M. J.
    Clanton, D.
    Buckheit, R. W.
    Covell, D. G.
    Wallqvist, A.
    McDonnell, N. B.
    Deguzman, R. N.
    Summers, M. F.
    Zalkow, L.
    Bader, J. P.
    Haugwitz, R. D.
    Sausville, E. A.

  2. Author Address

    Rice WG NCI FREDERICK CANC RES & DEV CTR SAIC FREDERICK LAB ANTIVIRAL DURG MECHANISMS FREDERICK, MD 21702 USA NCI FREDERICK CANC RES & DEV CTR SAIC FREDERICK ANTI AIDS VIRUS DRUG SCREENING LAB FREDERICK, MD 21702 USA FREDERICK RES CTR SO RES INST VIROL RES GRP FREDERICK, MD 21701 USA SAIC FREDERICK NCI FREDERICK CANC RES & DEV CTR DIV BASIC SCI FREDERICK, MD 21702 USA UNIV MARYLAND BALTIMORE CTY HOWARD HUGHES MED INST BALTIMORE, MD 21228 USA UNIV MARYLAND BALTIMORE CTY DEPT CHEM & BIOCHEM BALTIMORE, MD 21228 USA GEORGIA INST TECHNOL DEPT CHEM ATLANTA, GA 30332 USA NCI DEV THERAPEUT PROGRAM DIV CANC TREATMENT DIAG & CTR BETHESDA, MD 20892 USA
    1. Year: 1997
  2. Journal: Nature Medicine
    1. 3
    2. 3
    3. Pages: 341-345
  4. Type of Article: Article
  1. Abstract:

    Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)(2)-Cys-(X)(4)-His-(X)(4)-Cys (CCHC)(1,2). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapsid CCHC zinc fingers are highly conserved among retroviruses(1,3,4). These CCHC domains are required during both the early(5,6) and late(7,8) phases of retroviral replication, making them attractive targets for antiviral agents. Toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains(9-14). Such nucleocapsid inhibitors were directly virucidal by preventing the initiation of reverse transcription(15) and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors(16). Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al.(17) also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization. [References: 20]

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