       Document 0211
 DOCN  M9640211
 TI    Oltipraz, a novel inhibitor of human immunodeficiency virus type 1
       (HIV-1) replication.
 DT    9604
 AU    Prochaska HJ; Chavan SJ; Baron P; Polsky B; Molecular Pharmacology and
       Therapeutics Program, Memorial; Sloan-Kettering Cancer Center, New York,
       NY 10021, USA.
 SO    J Cell Biochem Suppl. 1995;22:117-25. Unique Identifier : AIDSLINE
       MED/96010322
 AB    Glutathione (GSH) levels are markedly depleted in patients infected with
       human immunodeficiency virus type 1 (HIV-1) and supplementation of media
       with high concentrations (5-20 mM) of low-molecular weight thiols
       prevents HIV-1 replication in cultured cells. We were intrigued whether
       chemopreventive enzyme inducers might represent a more pharmacologically
       feasible method to inhibit HIV-1 replication since these compounds
       elevate intracellular concentrations of GSH at nontoxic doses in vivo.
       After establishing that all inducers surveyed were able to elevate GSH
       levels in human T-cell and monocytoid cell lines, we were surprised to
       find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was
       uniquely able to inhibit HIV-1 replication (IC50 = 5-15 microM).
       Oltipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to
       inhibit acute HIV-1 replication by inactivating reverse transcriptase
       (RT). However, among DTTs that inhibit HIV-1 replication in acutely
       infected cells, only oltipraz was able to inhibit HIV-1 replication in a
       chronic infection model. Thus, in addition to inactivating RT, oltipraz
       appears to have an additional antiviral mechanism distal to viral
       integration. Our laboratories are attempting to determine the mechanism
       by which oltipraz inhibits HIV-1 replication in chronically infected
       cells; we are also attempting to determine the bioorganic mechanism for
       the inactivation of RT. Since the covalent modification of schistosomal
       proteins and transcription factor(s) are thought to be responsible for
       the antiparasitic and chemopreventive activities of DTTs, respectively,
       our studies should be relevant to understanding the diverse medicinal
       properties of DTTs. Oltipraz, an antischistosomal drug undergoing
       clinical evaluation as an anticarcinogen, inhibits HIV-1 replication at
       concentrations achievable in human serum. It is intriguing to consider
       oltipraz as a therapeutic agent not only for its antiretroviral
       activity, but also for the prevention of HIV-1 associated neoplasms.
 DE    Acquired Immunodeficiency Syndrome/DRUG THERAPY  Acute Disease
       Antiviral Agents/*THERAPEUTIC USE  Clinical Trials  Human
       HIV-1/*PHYSIOLOGY  Pyrazines/*THERAPEUTIC USE
       Schistosomicides/*THERAPEUTIC USE  Support, Non-U.S. Gov't  Support,
       U.S. Gov't, P.H.S.  Virus Replication/*DRUG EFFECTS  JOURNAL ARTICLE
       REVIEW  REVIEW, TUTORIAL

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

