Characterization of Novel Human Hepatoma Cell Lines with Stable Hepatitis B Virus Secretion for Evaluating New Compounds against Lamivudine- and Penciclovir-Resistant Virus

2区 · 医学

Article

作者: Fu, Lei ; Cheng, Yung-Chi

ABSTRACTl-Nucleoside analogs are new therapeutic agents for treatment of chronic hepatitis B. However, their clinical application was limited by the emergence of viral resistance. It is important to develop a new system to evaluate drug cross-resistance and to test new agents that may overcome resistant virus. In this report, three cell lines HepG2-WT10, HepG2-SM1, and HepG2-DM2 are presented; these cell lines were established by transfection of HepG2 cells with unique fully functional 1.1× hepatitis B virus (HBV) genomes: wild-type HBV-adr and its L526M and L526MM550V variants, respectively. We have demonstrated that these genomes have different susceptibilities to lamivudine [l(−)SddC] and penciclovir (PCV). By examining HBV RNA transcription, antigen expression, progeny DNA replication, and viral susceptibilities tol(−)SddC, PCV, and other nucleoside analogs, it is concluded that the cell lines are able to stably producel(−)SddC- and PCV-sensitive and -resistant HBV virions. In addition, the relative susceptibilities of the wild-type and mutant HBV produced from the stably transfected cell lines to several anti-HBV nucleoside analogs were also examined and found to be about the same as those found by using a transient infection system. PMEA [9-(2-phosphonylmethoxytehyl)-adenine] and QYL685 are able to suppressl(−)SddC- and PCV-resistant HBV. In conclusion, this cell culture system is a novel and useful tool for evaluating anti-HBV compounds and biologics.

1999-10-01·Antimicrobial Agents and Chemotherapy2区 · 医学

In Vitro Induction of Human Immunodeficiency Virus Type 1 Variants Resistant to Phosphoralaninate Prodrugs of Z -Methylenecyclopropane Nucleoside Analogues

2区 · 医学

Article

作者: Mitsuya, Hiroaki ; Kavlick, Mark F. ; Kodama, Eiichi ; Feldman, Ron ; Qiu, Yao-Ling ; Zemlicka, Jiri ; Yoshimura, Kazuhisa

ABSTRACT Two methylenecyclopropane nucleoside analogues with a phenylphosphoralaninate moiety, QYL-685 and QYL-609, exert potent and specific activities against human immunodeficiency virus type 1 strain LAI (HIV-1 LAI ) and HIV-2 in vitro. In this study, we induced HIV-1 variants resistant to QYL-685 by exposing HIV-1 LAI to increasing concentrations of QYL-685. After 16 passages, the virus (HIV-1 P16 ) was less sensitive to QYL-685 (104-fold), QYL-609 (>41-fold), and (−)-β-2′,3′-dideoxy-3′-thiacytidine (3TC) (>1,100-fold) than was HIV-1 LAI and contained an M184I mutation. Two infectious clones, HIV-1 M184I and HIV-1 M184V , were resistant to QYL-685, QYL-609, and 3TC, confirming that the M184I mutation was responsible for the observed resistance. Viral-fitness analyses (competitive HIV-1 replication assays) revealed that in the absence of drugs, M184I and M184V conferred a replication disadvantage on the virus compared to the replication efficiency of the wild-type infectious clone (HIV-1 wt ). However, in the presence of QYL-685 (4 μM), HIV-1 M184I and HIV-1 M184V showed greater fitness than HIV-1 wt . These data may provide structural and virological relevance with regard to the emergence of M184I and M184V substitutions in HIV-1.

1999-06-01·Antimicrobial Agents and Chemotherapy2区 · 医学

In Vitro Anti-Human Immunodeficiency Virus Activities of Z - and E -Methylenecyclopropane Nucleoside Analogues and Their Phosphoro- l -Alaninate Diesters

2区 · 医学

Article

作者: Kodama, Eiichi N. ; Maroun, Victor ; Uchida, Hiroyuki ; Maeda, Yosuke ; Kosalaraksa, Pope ; Yoshimura, Kazuhisa ; Mitsuya, Hiroaki ; Qiu, Yao-Ling ; Zemlicka, Jiri

ABSTRACT Nucleoside analogues with a Z - or an E -methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro- l -alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 μM, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

100 项与 QYL-685 相关的药物交易

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