title: Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease.
abstract: A synthetic, symmetry-based inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, A77003, was evaluated for antiviral activity and cytotoxicity in vitro in human peripheral blood lymphocytes or cell lines H9, CEM, and U937. Toxicity and antiviral activity of the HIV-1 protease inhibitor were compared with those of the reverse transcriptase inhibitors zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine and human recombinant alpha and beta interferons. Production of infectious virus particles, cell-free p24 antigen, and cell-associated viral proteins was reduced 50% by the HIV-1 protease inhibitor at concentrations of 0.12 to 0.26 microM (50% effective concentration [EC50]) in acute infection and 0.2 to 1.7 microM (EC50) in persistent infection. Fluorescence-activated cell sorter analysis of U937 cells persistently infected with HIVIIIB using a monoclonal antibody to HIV also showed a reduction of cell-associated viral protein in A77003-treated cells. Furthermore, toxicity of A77003 assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was not observed at greater than 100 times the EC50. A77003 was more effective in persistent HIV-1 infection than alpha and beta interferons (1,000 U/ml), while zidovudine and 2',3'-dideoxy-2',3'-didehydrothymidine were not active.
authors.affiliation: Department of Pathology, School of Medicine, University of Maryland, Baltimore 21201.
authors.forename: J J
authors.initials: JJ
authors.lastname: Kort
authors.forename: J A
authors.initials: JA
authors.lastname: Bilello
authors.forename: G
authors.initials: G
authors.lastname: Bauer
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016655:HIV Core Protein p24 / Q000032:analysis; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D007118:Immunoassay; D008782:Methylurea Compounds; D011725:Pyridines; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D011725:Pyridines; C079555:Abbott 77003; D014633:Valine