Cell-Based and Biochemical Analysis of the anti-HIV Activity of Combinations of 3′-azido-3′-deoxythymidine and Analogues of TIBO

• Published in: Antiviral chemistry & chemotherapy 1994-02, Vol.5 (1), p.35-42
• Main Authors: Buckheit, R. W., White, E. L., Germany-Decker, J., Allen, L. B., Ross, L. J., Shannon, W. M., Janssen, P. A. J., Chirigos, M. A.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral activity; Antiviral agents; Biochemical analysis; Biological and medical sciences; Cell culture; Chemotherapy; Drug resistance; HIV; Human immunodeficiency virus; Medical sciences; Pharmacology. Drug treatments; Resistant mutant; RNA-directed DNA polymerase; Toxicity; Zidovudine
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632029400500105

The toxicity of 3′-azido-3′-deoxythymidine (AZT) and the appearance of drug-resistant mutants in patients treated with AZT emphasizes the critical importance of the development of alternative strategies for the therapy of AIDS patients. Combination antiviral chemotherapy provides an attractive therapeutic strategy since the dose of the individual agents may be lowered to reduce toxicity and the use of two potent antiviral agents may limit the development of drug resistance. Two analogues of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO) potently and selectively inhibit the replication of HIV-1 in cell culture. In combination with AZT, either of the two TIBO compounds, R82913 and R86183, was highly synergistic in cell culture against HIV-1. However, in biochemical enzyme inhibition assays, utilizing recombinant HIV-1 reverse transcriptase, synergy was not detected at the enzymatic level. These results suggest that one of these two known inhibitors of HIV-1 reverse transcriptase may have a secondary mechanism of action distinct from inhibition of the reverse transcriptase.