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4′‐modified nucleoside analogs: Potent inhibitors active against entecavir‐resistant hepatitis B virus
Author(s) -
Takamatsu Yuki,
Tanaka Yasuhito,
Kohgo Satoru,
Murakami Shuko,
Singh Kamalendra,
Das Debananda,
Venzon David J.,
Amano Masayuki,
HigashiKuwata Nobuyo,
Aoki Manabu,
Delino Nicole S.,
Hayashi Sanae,
Takahashi Satoru,
Sukenaga Yoshikazu,
Haraguchi Kazuhiro,
Sarafianos Stefan G.,
Maeda Kenji,
Mitsuya Hiroaki
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27962
Subject(s) - entecavir , ic50 , virology , hepatitis b virus , viremia , nucleoside , nucleoside analogue , chemistry , virus , microbiology and biotechnology , biology , in vitro , lamivudine , biochemistry
Certain nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV‐1) and hepatitis B virus (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more‐potent agents that offer profound viral suppression. Here, we report that 4′‐C‐cyano‐2‐amino‐2′‐deoxyadenosine (CAdA) is a novel, highly potent inhibitor of both HBV (half maximal inhibitory concentration [IC 50 ] = 0.4 nM) and HIV‐1 (IC 50 = 0.4 nM). In contrast, the approved anti‐HBV NRTI, entecavir (ETV), potently inhibits HBV (IC 50 = 0.7 nM), but is much less active against HIV‐1 (IC 50 = 1,000 nM). Similarly, the highly potent HIV‐1 inhibitor, 4′‐ethynyl‐2‐fluoro‐2′‐deoxyadenosine (EFdA; IC 50 = 0.3 nM) is less active against HBV (IC 50 = 160 nM). Southern analysis using Huh‐7 cells transfected with HBV‐containing plasmids demonstrated that CAdA was potent against both wild‐type (IC 50 = 7.2 nM) and ETV‐resistant HBV (IC 50 = 69.6 nM forHBV ETV ‐ R L 180 M / S 202 G / M 204 V ), whereas ETV failed to reduceHBV ETV ‐ R L 180 M / S 202 G / M 204 VDNA even at 1 μM. Once‐daily peroral administration of CAdA reducedHBV ETV ‐ R L 180 M / S 202 G / M 204 Vviremia ( P = 0.0005) in human‐liver‐chimeric/ HBV ETV ‐ R L 180 M / S 202 G / M 204 V –infected mice, whereas ETV completely failed to reduceHBV ETV ‐ R L 180 M / S 202 G / M 204 Vviremia. 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. (H epatology 2015;62:1024‐1036)