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Anti-human immunodeficiency virus type 1 activity of novel 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2012 May; Vol. 56 (5), pp. 2581-9. Date of Electronic Publication: 2012 Jan 30. - Publication Year :
- 2012
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Abstract
- Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replication in vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed that AmBBU requires the amino acid residues Leu100, Val106, Tyr181, and Trp229 for exerting its inhibitory effect on HIV-1. Four additional amino acid changes (K451R, R461K, T468P, and D471N) were identified in the RNase H domain of RT; however, their precise role in the acquisition of resistance is still unclear. In conclusion, the initial mutation Y181C seems sufficient for the acquisition of resistance to the uracil derivatives AzBBU and AmBBU. Further studies are required to determine the precise role of each mutation in the acquisition of HIV-1 resistance.
- Subjects :
- Amino Acid Sequence
Amino Acid Substitution
Anti-HIV Agents chemistry
Anti-HIV Agents metabolism
Binding Sites
Cell Line
Computer Simulation
Drug Resistance, Viral drug effects
Drug Resistance, Viral genetics
HIV Reverse Transcriptase chemistry
HIV Reverse Transcriptase metabolism
HIV-1 enzymology
HIV-1 genetics
Humans
Models, Molecular
Molecular Sequence Data
Mutation
Protein Structure, Tertiary
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors metabolism
Sequence Analysis
Small Molecule Libraries
T-Lymphocytes drug effects
T-Lymphocytes virology
Uracil chemistry
Uracil metabolism
Uracil pharmacology
Anti-HIV Agents pharmacology
HIV Reverse Transcriptase antagonists & inhibitors
HIV-1 drug effects
Reverse Transcriptase Inhibitors pharmacology
Uracil analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 56
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 22290950
- Full Text :
- https://doi.org/10.1128/AAC.06307-11