       Document 0022
 DOCN  M9610022
 TI    Inhibition of the human immunodeficiency virus-1 protease and human
       immunodeficiency virus-1 replication by bathocuproine disulfonic acid
       Cu1+.
 DT    9601
 AU    Davis DA; Branca AA; Pallenberg AJ; Marschner TM; Patt LM; Chatlynne LG;
       Humphrey RW; Yarchoan R; Levine RL; Laboratory of Biochemistry, National
       Heart, Lung, and Blood; Institute, National Institutes of Health,
       Bethesda, Maryland; 20892-0320, USA.
 SO    Arch Biochem Biophys. 1995 Sep 10;322(1):127-34. Unique Identifier :
       AIDSLINE MED/96004788
 AB    The protease encoded by the human immunodeficiency virus-1 (HIV-1) is
       essential for processing viral polyproteins which contain the enzymes
       and structural proteins required for the infectious virus. It was
       previously found that cupric chloride, in the presence of dithiothreitol
       or ascorbic acid, could inhibit the HIV-1 protease. It was suggested
       that a Cu1+ chelate was the moiety responsible for inhibition of the
       protease. This hypothesis has now been investigated directly by
       utilizing the stable Cu1+ chelate, bathocuproine disulfonic acid Cu1+
       (BCDS-Cu1+). BCDS-Cu1+ inhibited the HIV-1 wild type protease as well as
       a mutant HIV-1 protease lacking cysteines. BCDS-Cu1+ was a competitive
       inhibitor of the mutant HIV-1 protease with an apparent Ki of 1 microM.
       Replication of HIV-1 in human lymphocytes and the cytotoxic effect of
       HIV-1 in CEM cells was inhibited by micromolar BCDS-Cu1+. Inhibition of
       the protease and of HIV replication by BCDS-Cu1+ was dependent on the
       presence of Cu1+ as BCDS alone was ineffective. EDTA blocked the
       inhibition of the protease by Cu1+ but was unable to block inhibition of
       the protease by BCDS-Cu1+, indicating that the Cu1+ complex was the
       inhibitory agent. The apparent IC50 for BCDS-Cu1+ on the inhibition of
       replication by primary isolates of HIV-1 was 5 microM. However,
       BCDS-Cu1+ did not affect polyprotein processing in an H9 cell line
       chronically infected with HIV-1, indicating that BCDS-Cu1+ acts by yet
       another mechanism to block HIV infection. Other possible targets for
       BCDS-Cu1+ include inhibition of viral adsorption and/or inhibition of
       the HIV-1 integrase.
 DE    Antiviral Agents/PHARMACOLOGY  Cell Line  Chelating Agents/*PHARMACOLOGY
       Copper/*PHARMACOLOGY  Edetic Acid/PHARMACOLOGY  Human  HIV
       Protease/GENETICS  HIV Protease Inhibitors/*PHARMACOLOGY  HIV-1/*DRUG
       EFFECTS/ISOLATION & PURIF/PHYSIOLOGY  In Vitro  Kinetics  Leukocytes,
       Mononuclear  Macrophages  Mutagenesis, Site-Directed
       Phenanthrolines/*PHARMACOLOGY  Renin/METABOLISM  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).

