Inhibition of Hepatitis B Virus (HBV) Replication by Pyrimidines Bearing an Acyclic Moiety: Effect on Wild-Type and Mutant HBV
| Autor: | Wassila Semaine, D. Lorne Tyrrell, Monika Johar, Rakesh K. Kumar, Babita Agrawal |
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| Rok vydání: | 2006 |
| Předmět: |
Hepatitis B virus
medicine.drug_class Virus Replication medicine.disease_cause Antiviral Agents Virus Cell Line Structure-Activity Relationship chemistry.chemical_compound Orthohepadnavirus Chlorocebus aethiops Drug Resistance Viral Drug Discovery medicine Animals Humans Moiety Glycosyl biology Pyrimidine Nucleosides biology.organism_classification Virology Ducks chemistry Hepadnaviridae Viral replication Lamivudine Mutation Molecular Medicine Antiviral drug |
| Zdroj: | Journal of Medicinal Chemistry. 49:2049-2054 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm058271d |
| Popis: | Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The main clinical limitation of a current antiviral drug for HBV, lamivudine, is the emergence of drug-resistant viral strains upon prolonged therapy. A group of 5-, 6-, or 5,6-substituted acyclic pyrimidine nucleosides with a 1-[(2-hydroxyethoxy)methyl] moiety were synthesized and evaluated for antiviral activities. The target compounds were prepared by the reaction of silylated uracils possessing a variety of substituents at the C-5 or C-6 positions or both with 1,3-dioxolane in the presence of potassium iodide and chlorotrimethylsilane by a convenient and single-step synthesis. Among the compounds tested, 5-chloro and 5-bromo analogues possessing an acyclic glycosyl moiety were the most effective and selective antiviral agents in the in vitro assays against wild-type duck HBV (EC50=0.4-2.2 and 3.7-18.5 microM, respectively) and human HBV-containing 2.2.15 cells (EC50=4.5-45.4 and 18.5-37.7 microM, respectively). These compounds were also found to retain sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and double mutations (L180M/M204V). The compounds investigated did not show cytotoxicity to host HepG2 and Vero cells, up to the highest concentration tested. The results presented here confirm and accentuate the potential of acyclic pyrimidine nucleosides as anti-HBV agents and extend our previous observations. We herein report the capability of acyclic pyrimidine nucleosides to inhibit the replication of both wild-type and drug-resistant mutant HBV. |
| Databáze: | OpenAIRE |
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