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NS5B

About: NS5B is a research topic. Over the lifetime, 1314 publications have been published within this topic receiving 59534 citations.


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Journal ArticleDOI
TL;DR: QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs, and shows that NIs are always more reactive than their parent nucleotide.
Abstract: Quantitative structure–activity relationship (QSAR) parameters are good indicators for the reactivity of direct-acting antiviral drugs. Since molecular structure is related to molecular function, careful selection of molecular substitutions will result in more drugs that are potent. In this work, QSAR parameters are selected in order to compare the four drugs used as nucleotide inhibitors (NIs) for non-structural 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). These drugs are: ribavirin (widely used over the last 20 years), sofosbuvir (approved on December 2013 by FDA), and finally IDX-184 and R7128 (phase IIb of clinical trial drugs). The nucleotide analogues uracil (U), guanine (G), and cytosine (C) from which these drugs are fabricated are also compared to that group of drugs. QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs. It also shows that NIs are always more reactive than their parent nucleotide. The active site environment of 12 amino acids coordinated with IDX-184 through two Mg2+. The interaction with HCV subtypes 1a, 2b, and 3b is better than 4a subtype.

29 citations

Journal ArticleDOI
TL;DR: These studies strongly suggest that HCV non-structural proteins, with the exception of NS5A, can only act in cis on the RNA from which they were translated.

29 citations

Journal ArticleDOI
TL;DR: The tree shrew can be used as an animal model supporting the infection and replication of HCV in vitro and in vivo, and five sense mutations suggested that HCV undergoes genetic evolution during culture.
Abstract: The tree shrew (Tupaia belangeri chinensis), a small animal widely distributed in Southeast Asia and southwest China, has the potential to be developed as an animal model for hepatitis C. To determine the susceptibility of the tree shrew to hepatitis C virus (HCV) infection in vitro and in vivo, a well-established HCV, produced from the J6/JFH1-Huh7.5.1 culture system, was used to infect cultured primary tupaia hepatocytes (PTHs) and tree shrews. The in vitro results showed that HCV genomic RNA and HCV-specific nonstructural protein 5A (NS5A) could be detected in the PTH cell culture from days 3–15 post-infection, although the viral load was lower than that observed in Huh7.5.1 cell culture. The occurrence of five sense mutations [S391A, G397A, L402F and M405T in the hypervariable region 1 (HVR1) of envelope glycoprotein 2 and I2750M in NS5B] suggested that HCV undergoes genetic evolution during culture. Fourteen of the 30 experimental tree shrews (46.7 %) were found to be infected, although the HCV viremia was intermittent in vivo. A positive test for HCV RNA in liver tissue provided stronger evidence for HCV infection and replication in tree shrews. The results of an immunohistochemistry assay also demonstrated the presence of four HCV-specific proteins (Core, E2, NS3/4 and NS5A) in the hepatocytes of infected tree shrews. The pathological changes observed in the liver tissue of infected tree shrews could be considered to be representative symptoms of mild hepatitis. These results revealed that the tree shrew can be used as an animal model supporting the infection and replication of HCV in vitro and in vivo.

29 citations

Journal ArticleDOI
25 Nov 2005-Virology
TL;DR: The results suggest that SL RNA decoys may prove to be useful in the treatment of hepatitis C, which may be advantageous over other sequence-specific gene therapy modalities in preventing the escape of genetic variants.

29 citations

Journal ArticleDOI
TL;DR: It is demonstrated that the viral p7 and NS5B proteins cooperate to promote virion infectivity by decreasing sphingomyelin content in the virion.
Abstract: The molecular mechanisms that govern hepatitis C virus (HCV) assembly, release, and infectivity are still not yet fully understood. In the present study, we sequenced a genotype 2A strain of HCV (JFH-1) that had been cell culture adapted in Huh-7.5 cells to produce nearly 100-fold-higher viral titers than the parental strain. Sequence analysis identified nine mutations in the genome, present within both the structural and nonstructural genes. The infectious clone of this virus containing all nine culture-adapted mutations had 10-fold-higher levels of RNA replication and RNA release into the supernatant but had nearly 1,000-fold-higher viral titers, resulting in an increased specific infectivity compared to wild-type JFH-1. Two mutations, identified in the p7 polypeptide and NS5B RNA-dependent RNA polymerase, were sufficient to increase the specific infectivity of JFH-1. We found that the culture-adapted mutation in p7 promoted an increase in the size of cellular lipid droplets following transfection of viral RNA. In addition, we found that the culture-adaptive mutations in p7 and NS5B acted synergistically to enhance the specific viral infectivity of JFH-1 by decreasing the level of sphingomyelin in the virion. Overall, these results reveal a genetic interaction between p7 and NS5B that contributes to virion specific infectivity. Furthermore, our results demonstrate a novel role for the RNA-dependent RNA polymerase NS5B in HCV assembly. Importance Hepatitis C virus assembly and release depend on viral interactions with host lipid metabolic pathways. Here, we demonstrate that the viral p7 and NS5B proteins cooperate to promote virion infectivity by decreasing sphingomyelin content in the virion. Our data uncover a new role for the viral RNA-dependent RNA polymerase NS5B and p7 proteins in contributing to virion morphogenesis. Overall, these findings are significant because they reveal a genetic interaction between p7 and NS5B, as well as an interaction with sphingomyelin that regulates virion infectivity. Our data provide new strategies for targeting host lipid-virus interactions as potential targets for therapies against HCV infection.

29 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202310
202258
202128
202033
201943
201842