       Document 0151
 DOCN  M9640151
 TI    Antiviral properties of simple difunctionalized enols targeted to the
       HIV-1 protease.
 DT    9604
 AU    Vaillancourt M; Sauve G; Cohen E; Departement de Microbiologie et
       d'Immunologie, Universite de; Montreal, Quebec, Canada.
 SO    Antiviral Res. 1995 Jun;27(3):205-18. Unique Identifier : AIDSLINE
       MED/96145331
 AB    The human immunodeficiency virus type 1 (HIV-1) protease catalyses the
       specific cleavage of the virion structural polyproteins p55gag and
       p160gag-pol and is, therefore, essential for viral maturation. We have
       previously reported a series of low molecular weight non-peptidic
       enol-based compounds that inhibit the HIV-1 protease activity in a
       competitive fashion (Vaillancourt et al., Bioorg. Med. Chem., 2 (1994)
       343-355). Here we demonstrate that VS-215 and VS-261, two of these
       non-peptidic inhibitors, impair viral polyprotein maturation and exhibit
       antiviral activity in infected MT4 cells. The ID50 for these two
       compounds ranged between 24 and 50 microM whereas their TD50 ranged
       between 60 and 200 microM depending on the cell lines used. The
       calculated therapeutic index of these two inhibitors both had values of
       2.5 even though they were shown to be non cytotoxic at their ID50. Their
       calculated permeability index ranged between 0.09 and 0.79 suggesting
       that these enol-based inhibitors efficiently reach the site of protease
       activity. These results provide new information on the therapeutic
       potential of this new class of protease inhibitors and emphasize the
       usefulness of enol chemistry in the development of anti-HIV-1 protease
       inhibitors.
 DE    Animal  Antiviral Agents/*PHARMACOLOGY/TOXICITY  Cell Line
       Cercopithecus aethiops  Cross-Linking Reagents  Gene Products,
       gag/BIOSYNTHESIS/DRUG EFFECTS  Human  HIV Protease
       Inhibitors/*PHARMACOLOGY/TOXICITY  HIV-1/*DRUG EFFECTS
       Nitriles/*PHARMACOLOGY/TOXICITY  Protein Precursors/BIOSYNTHESIS/DRUG
       EFFECTS  Support, Non-U.S. Gov't  Virus Replication/DRUG EFFECTS
       JOURNAL ARTICLE

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

