Structure−Activity Relationship of Purine Ribonucleosides for Inhibition of Hepatitis C Virus RNA-Dependent RNA Polymerase
| Autor: | Michele Bosserman, Neelima Bhat, Joanne E Tomassini, Sanjib Bera, Marija Prhavc, Christine Burlein, Malcolm MacCoss, Charles R. Allerson, Jennifer L. Brooks, David B. Olsen, Jie Xia, Balkrishen Bhat, C. Frank Bennett, Steven S. Carroll, P. Dan Cook, Quanlai Song, Krista Getty, Anne B. Eldrup, Daniel R. McMasters, Thazha P. Prakash |
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| Rok vydání: | 2004 |
| Předmět: |
Adenosine Deaminase
Guanine Ribose Hepatitis C virus Molecular Conformation RNA-dependent RNA polymerase Purine nucleoside phosphorylase Hepacivirus Viral Nonstructural Proteins medicine.disease_cause Methylation Structure-Activity Relationship chemistry.chemical_compound Adenosine deaminase RNA polymerase Drug Discovery medicine NS5B biology Hydrogen Bonding Purine Nucleosides RNA-Dependent RNA Polymerase Molecular biology Purine-Nucleoside Phosphorylase chemistry Biochemistry Purines biology.protein Molecular Medicine Ribonucleosides Nucleoside |
| Zdroj: | Journal of Medicinal Chemistry. 47:2283-2295 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2'-C-Methyladenosine and 2'-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure-activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2'- and 3'-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2'-C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism. |
| Databáze: | OpenAIRE |
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