Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease

J. J. Kort, J. A. Bilello, Gerhard Bauer, G. L. Drusano

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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 μM (50% effective concentration [EC50]) in acute infection and 0.2 to 1.7 μM (EC50) in persistent infection. Fluorescence-activated cell sorter analysis of U937 cells persistently infected with HIV(IIIB) 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.

Original languageEnglish (US)
Pages (from-to)115-119
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume37
Issue number1
StatePublished - 1993
Externally publishedYes

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Abbott 77003
Antiviral Agents
HIV-1
Peptide Hydrolases
Zidovudine
Interferon-beta
Viral Proteins
Protease Inhibitors
Interferon-alpha
HIV
U937 Cells
Reverse Transcriptase Inhibitors
Virus Diseases
Infection
Virion
Fluorescence
Monoclonal Antibodies
Lymphocytes
Antigens
Cell Line

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Preclinical evaluation of antiviral activity and toxicity of Abbott A77003, an inhibitor of the human immunodeficiency virus type 1 protease. / Kort, J. J.; Bilello, J. A.; Bauer, Gerhard; Drusano, G. L.

In: Antimicrobial Agents and Chemotherapy, Vol. 37, No. 1, 1993, p. 115-119.

Research output: Contribution to journalArticle

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