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Hepatology. 2015 Jun 29. doi: 10.1002/hep.27962. [Epub ahead of print]
4'-modified nucleoside analogs: Potent inhibitors active against entecavir-resistant hepatitis B virus.Takamatsu Y1, Tanaka Y2, Kohgo S3,4, Murakami S2, Singh K5, Das D1, Venzon DJ6, Amano M7, Kuwata N3,7, Aoki M1,7,8, Delino NS1, Hayashi S2, Takahashi S9, Sukenaga Y3, Haraguchi K4, Sarafianos SG5, Maeda K1,3, Mitsuya H1,3,7.
Author information
- 1Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- 2Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
- 3Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
- 4Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan.
- 5Molecular Microbiology & Immunology, School of Medicine, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
- 6Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- 7Departments of Hematology, Rheumatology, and Clinical Immunology & Infectious Disease, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
- 8Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan.
- 9Department of Experimental Pathology & Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
AbstractNucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against HIV-1 and HBV. However, both viruses often acquire NRTI resistance, making it crucial to develop more potent agents that offer profound viral suppression. We report here that 4'-C-cyano-2-amino-2'-deoxyadenosine (CAdA) is a novel highly potent inhibitor of both HBV (IC50 =0.4 nM) and HIV-1 (IC50 =0.4 nM). In contrast, the approved anti-HBV NRTI entecavir (ETV) potently inhibits HBV (IC50 =0.7 nM) but is much less active against HIV-1 (IC50 =1,000 nM). Similarly, the highly potent HIV-1 inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) (IC50 =0.3 nM) is less active against HBV (IC50 =160 nM). Southern analysis using Huh-7 cells transfected with HBV-containing plasmids demonstrated that CAdA was potent against both wild-type (IC50 =7.2 nM) and ETV-resistant HBV (IC50 =69.6 nM for HBVETV-R L180M/S202G/M204V ), whereas ETV failed to reduce HBVETV-R L180M/S202G/M204V DNA even at 1 μM. Once daily peroral administration of CAdA reduced HBVETV-R L180M/S202G/M204V viremia (p=0.0005) in human-liver-chimeric/HBVETV-R L180M/S202G/M204V -infected mice, while ETV completely failed to reduce HBVETV-R L180M/S202G/M204V viremia. None of the mice had significant drug-related body-weight or serum human-albumin concentration changes. Molecular modeling suggests that a shallower HBV-RT hydrophobic pocket at the polymerase active site can better accommodate the slightly shorter 4'-cyano of CAdA-triphosphate (TP), but not the longer 4'-ethynyl of EFdA-TP. In contrast, the deeper HIV-1-RT pocket can efficiently accommodate the 4'-substitutions of both NRTIs. The ETV-TP's cyclopentyl ring can bind more efficiently at the shallow HBV-RT binding pocket.
CONCLUSION: These data provide insights on the structural and functional associations of HBV- and HIV-1-RTs and show that CAdA may offer new therapeutic options for HBV patients. This article is protected by copyright. All rights reserved.
© 2015 by the American Association for the Study of Liver Diseases.
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发表于 2015-7-1 18:40
