Document 0596
 DOCN  M9650596
 TI    The in vitro ejection of zinc from human immunodeficiency virus (HIV)
       type 1 nucleocapsid protein by disulfide benzamides with cellular
       anti-HIV activity.
 DT    9605
 AU    Tummino PJ; Scholten JD; Harvey PJ; Holler TP; Maloney L; Gogliotti R;
       Domagala J; Hupe D; Department of Biochemistry, Parke-Davis
       Pharmaceutical Research,; Division of Warner Lambert Co., Ann Arbor, MI
       48105, USA.
 SO    Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):969-73. Unique Identifier :
       AIDSLINE MED/96165501
 AB    Several disulfide benzamides have been shown to possess wide-spectrum
       antiretroviral activity in cell culture at low micromolar to
       submicromolar concentrations, inhibiting human immunodeficiency virus
       (HIV) type 1 (HIV-1) clinical and drug-resistant strains along with
       HIV-2 and simian immunodeficiency virus [Rice, W. G., Supko, J. G.,
       Malspeis, L., Buckheit, R. W., Jr., Clanton, D., Bu, M., Graham, L.,
       Schaeffer, C. A., Turpin, J. A., Domagala, J., Gogliotti, R., Bader, J.
       P., Halliday, S. M., Coren, L., Sowder, R. C., II, Arthur, L. O. &
       Henderson, L. E. (1995) Science 270, 1194-1197]. Rice and coworkers have
       proposed that the compounds act by attacking the two zinc fingers of HIV
       nucleocapsid protein. Shown here is evidence that low micromolar
       concentrations of the anti-HIV disulfide benzamides eject zinc from HIV
       nucleocapsid protein (NCp7) in vitro, as monitored by the zinc-specific
       fluorescent probe N-(6-methoxy-8-quinoyl)-p-toluenesulfonamide (TSQ).
       Structurally similar disulfide benzamides that do not inhibit HIV-1 in
       culture do not eject zinc, nor do analogs of the antiviral compounds
       with the disulfide replaced with a methylene sulfide. The kinetics of
       NCp7 zinc ejection by disulfide benzamides were found to be nonsaturable
       and biexponential, with the rate of ejection from the C-terminal zinc
       finger 7-fold faster than that from the N-terminal. The antiviral
       compounds were found to inhibit the zinc-dependent binding of NCp7 to
       HIV psi RNA, as studied by gel-shift assays, and the data correlated
       well with the zinc ejection data. Anti-HIV disulfide benzamides
       specifically eject NCp7 zinc and abolish the protein's ability to bind
       psi RNA in vitro, providing evidence for a possible antiretroviral
       mechanism of action of these compounds. Congeners of this class are
       under advanced preclinical evaluation as a potential chemotherapy for
       acquired immunodeficiency syndrome.
 DE    Amino Acid Sequence  Aminoquinolines  Antiviral Agents/*PHARMACOLOGY
       Benzamides/*PHARMACOLOGY  Capsid/DRUG EFFECTS/*METABOLISM  Cloning,
       Molecular  Comparative Study  Disulfides/*PHARMACOLOGY  Fluorescent Dyes
       Human  HIV-1/DRUG EFFECTS/*METABOLISM  Kinetics  Molecular Sequence Data
       Recombinant Proteins/DRUG EFFECTS/METABOLISM  Structure-Activity
       Relationship  Tosyl Compounds  Tryptophan  Viral Core Proteins/DRUG
       EFFECTS/*METABOLISM  Zinc/*METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).