更新于：2024-11-01

NS5B polymerase x RNA聚合酶

更新于：2024-11-01

基本信息

关联

项与 NS5B polymerase x RNA聚合酶相关的药物

GSK-5852

靶点

NS5B polymerase x RNA聚合酶

作用机制

NS5B polymerase抑制剂 [+1]

在研机构-

原研机构

GSK Plc

在研适应症-

非在研适应症

慢性丙型肝炎

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

GL-59728

靶点

NS5B polymerase x RNA聚合酶

作用机制

NS5B polymerase抑制剂 [+1]

在研机构-

原研机构

Genelabs Technologies, Inc.

在研适应症-

非在研适应症

丙型肝炎

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 NS5B polymerase x RNA聚合酶相关的临床试验

NCT01332552 / Terminated临床1期

A Randomized, Double Blind, Dose Escalation, Fusion, First Time in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Single and Repeat Doses of GSK2485852 in Chronically Infected Hepatitis C Subjects

GSK2485852 is a Hepatitis C NS5B site IV non-nucleoside polymerase inhibitor being developed for the treatment of chronic HCV infection. HBI115040 is the first administration of GSK2485852 in humans to establish the initial safety, tolerability, pharmacokinetic, and antiviral profile. The study design is a fusion of single and repeat dosing cohorts in HCV infected subjects to evaluate the safety, pharmacokinetics, and antiviral activity of GSK2485852.
HBI115040 describes a Phase I, randomized, double-blind, placebo-controlled, dose escalation fusion study to determine the safety, tolerability, pharmacokinetic, and antiviral profile of GSK2485852 in single doses (Part 1), repeat doses (Part 2), and ritonavir co-administration (Part 3) in chronically infected HCV subjects. The study will also explore the effect of a moderate (30%) fat meal on pharmacokinetic endpoints in HCV subjects in Part 1.

开始日期2011-01-14

申办/合作机构

GSK Plc

100 项与 NS5B polymerase x RNA聚合酶相关的临床结果

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100 项与 NS5B polymerase x RNA聚合酶相关的转化医学

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0 项与 NS5B polymerase x RNA聚合酶相关的专利（医药）

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项与 NS5B polymerase x RNA聚合酶相关的文献（医药）

2019-03-01·Virology3区 · 医学

Activation of protein kinase R by hepatitis C virus RNA-dependent RNA polymerase

3区 · 医学

Article

作者: Suzuki, Tetsuro ; Watashi, Koichi ; Aizaki, Hideki ; Shimoike, Takashi ; Matsuda, Mami ; Kato, Takanobu ; Muramatsu, Masamichi ; Wakita, Takaji ; Suzuki, Ryosuke

Hepatitis C virus (HCV) was shown to activate protein kinase R (PKR), which inhibits expression of interferon (IFN) and IFN-stimulated genes by controlling the translation of newly transcribed mRNAs. However, it is unknown exactly how HCV activates PKR. To address the molecular mechanism(s) of PKR activation mediated by HCV infection, we examined the effects of viral proteins on PKR activation. Here, we show that expression of HCV NS5B strongly induced PKR and eIF2α phosphorylation, and attenuated MHC class I expression. In contrast, expression of Japanese encephalitis virus RNA-dependent RNA polymerase did not induce phosphorylation of PKR. Co-immunoprecipitation analyses showed that HCV NS5B interacted with PKR. Furthermore, expression of NS5B with polymerase activity-deficient mutation failed to phosphorylate PKR, suggesting that RNA polymerase activity is required for PKR activation. These results suggest that HCV activates PKR by association with NS5B, resulting in translational suppression of MHC class I to establish chronic infection.

2013-07-02·Biochemistry3区 · 生物学

Molecular Simulations Illuminate the Role of Regulatory Components of the RNA Polymerase from the Hepatitis C Virus in Influencing Protein Structure and Dynamics

3区 · 生物学

Article

作者: Thorpe, Ian F. ; Davis, Brittny C.

The RNA polymerase (gene product NS5B) from the hepatitis C virus is responsible for replication of the viral genome and is a validated drug target for new therapeutic agents. NS5B has a structure resembling an open right hand (containing the fingers, palm, and thumb subdomains), a hydrophobic C-terminal region, and two magnesium ions coordinated in the palm domain. Biochemical data suggest that the magnesium ions provide structural stability and are directly involved in catalysis, while the C-terminus plays a regulatory role in NS5B function. Nevertheless, the molecular mechanisms by which these two features regulate polymerase activity remain unclear. To answer this question, we performed molecular dynamics simulations of NS5B variants with different C-terminal lengths in the presence or absence of magnesium ions to determine the impact on enzyme properties. We observed that metal binding increases both the magnitude and the degree of correlated enzyme motions. In contrast, we observed that the C-terminus restricts enzyme dynamics. Under certain conditions, our simulations revealed a fully closed conformation of NS5B that may facilitate de novo initiation of RNA replication. This knowledge is important because it fosters the development of a comprehensive description of RNA replication by NS5B and is relevant to understanding the functional properties of a broad class of related RNA polymerases such as 3D-pol from poliovirus. Ultimately, this information may also be pertinent to designing novel NS5B therapeutics.

2012-10-01·Biochemistry (Moscow)4区 · 生物学

Biogenic polyamines spermine and spermidine activate RNA polymerase and inhibit RNA helicase of hepatitis C virus

4区 · 生物学

Article

作者: A. V. Ivanov ; S. N. Kochetkov ; M. A. Khomutov ; A. R. Simonian ; A. R. Khomutov ; A. N. Korovina ; V. L. Tunitskaya

Influence of the biogenic polyamines spermine, spermidine, and putrescine as well as their derivatives on the replication enzymes of hepatitis C virus (HCV) was investigated. It was found that spermine and spermidine activate HCV RNA-dependent RNA polymerase (NS5B protein). This effect was not caused by the stabilization of the enzyme or by competition with template-primer complex, but rather it was due to achievement of true maximum velocity V(max). Natural polyamines and their derivatives effectively inhibited the helicase reaction catalyzed by another enzyme of HCV replication - helicase/NTPase (NS3 protein). However, these compounds affected neither the NTPase reaction nor its activation by polynucleotides. Activation of the HCV RNA polymerase and inhibition of the viral helicase were shown at physiological concentrations of the polyamines. These data suggest that biogenic polyamines may cause differently directed effects on the replication of the HCV genome in an infected cell.