       Document 0445
 DOCN  M9460445
 TI    Haloperidol-based irreversible inhibitors of the HIV-1 and HIV-2
       proteases.
 DT    9404
 AU    De Voss JJ; Sui Z; DeCamp DL; Salto R; Babe LM; Craik CS; Ortiz de
       Montellano PR; Department of Pharmaceutical Chemistry, School of
       Pharmacy,; University of California, San Francisco 94143-0446.
 SO    J Med Chem. 1994 Mar 4;37(5):665-73. Unique Identifier : AIDSLINE
       MED/94172612
 AB    The proteases expressed by the HIV-1 and HIV-2 viruses process the
       polyproteins encoded by the viral genomes into the mature proteins
       required for virion replication and assembly. Eight analogs of
       haloperidol have been synthesized that cause time-dependent inactivation
       of the HIV-1 protease and, in six cases, HIV-2 protease. The IC50 values
       for the analogues are comparable to that of haloperidol itself. Enzyme
       inactivation is due to the presence of an epoxide in two of the
       analogues and carbonyl-conjugated double or triple bonds in the others.
       Irreversible inactivation is confirmed by the failure to recover
       activity when one of the inhibitors is removed from the medium. At pH
       8.0, the agents inactivate the HIV-1 protease 4-80 times more rapidly
       than the HIV-2 protease. Faster inactivation of the HIV-1 protease is
       consistent with alkylation of cysteine residues because the HIV-1
       protease has four such residues whereas the HIV-2 protease has none.
       Inactivation of the HIV-2 protease requires modification of non-cysteine
       residues. The similarities in the rates of inactivation of the HIV-2
       protease by six agents that have intrinsically different reactivities
       toward nucleophiles suggest that the rate-limiting step in the
       inactivation process is not the alkylation reaction itself. At least
       five of the agents inhibit polyprotein processing in an ex vivo cell
       assay system, but they are also toxic to the cells.
 DE    Acetic Acids/CHEMISTRY  Alkylation  Binding Sites  Cell Line  Epoxy
       Compounds/CHEMICAL SYNTHESIS  Glutathione/CHEMISTRY
       Haloperidol/*ANALOGS & DERIVATIVES  Hela Cells  Human  Hydrogen-Ion
       Concentration  HIV Protease/CHEMISTRY/METABOLISM  HIV Protease
       Inhibitors/*CHEMICAL SYNTHESIS/PHARMACOLOGY  HIV-1/*ENZYMOLOGY
       HIV-2/*ENZYMOLOGY  Ketones/CHEMICAL SYNTHESIS  Kinetics  Models,
       Molecular  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

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

