Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human and monetary costs of chronic hepatitis C and the complications arising from this disease emphasize the urgency to find a treatment for Hepatitis C Virus (HCV) infected patients. The current standard of treatment for patients chronically infected with HCV is combination therapy with pegylated interferon plus ribavirin. Recently, viral enzymes have become the target of efforts to develop small molecule inhibitors interfering with the essential steps in the life cycle of the virus. Amongst these enzymes the HCV-encoded NS5B RNA-dependent RNA polymerase (NS5B RdRp) is essential for viral replication and has been recognized as a prime target for therapeutic intervention. Several distinct classes of inhibitors of NS5B RdRp have been disclosed in the literature, including active site inhibitors such as nucleosides and pyrophosphate mimetics, as well as non-nucleoside inhibitors. The latter, based on the success of allosteric inhibitors in the treatment of HIV infection, have been developed into compounds which show activity in the subgenomic cell-culture assay of HCV replication. This review provides an account of the recent developments in this field.
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PMID:Allosteric inhibition of the hepatitis C virus NS5B RNA dependent RNA polymerase. 1678 2

The global prevalence of hepatitis C virus (HCV) infection and serious health consequences associated with chronic state of the disease have become a significant health problem worldwide. Currently, there is no vaccine to prevent the disease and no specific antiviral drug directed against HCV infection. The current standard of care, interferon-based therapies, both alone or in combination with ribavirin, has demonstrated limited success and is associated with undesirable side effects. Thus, the treatment of the chronic HCV infection represents an unmet medical need. With advances in the understanding of HCV replication and the crystal structures of the virally encoded enzymes, the HCV NS3/4A serine protease and the NS5B RNA-dependent RNA polymerase have emerged as ideal targets toward the control of the disease and the development of new anti-HCV agents. In this review, we will summarize the current treatment options, and outline the approaches toward discovery of small molecule antivirals against the virally encoded enzymes. The current clinical studies of promising lead compounds are also reviewed.
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PMID:Recent development of therapeutics for chronic HCV infection. 1682 88

The Reoviridae family represents a diverse collection of viruses with segmented double-stranded (ds)RNA genomes, including some that are significant causes of disease in humans, livestock, and plants. The genome segments of these viruses are never detected free in the infected cell but are transcribed and replicated within viral cores by RNA-dependent RNA polymerase (RdRP). Insight into the replication mechanism has been provided from studies on Rotavirus, a member of the Reoviridae whose RdRP can specifically recognize viral plus (+) strand RNAs and catalyze their replication to dsRNAs in vitro. These analyses have revealed that although the rotavirus RdRP can interact with recognition signals in (+) strand RNAs in the absence of other proteins, the conversion of this complex to one that can support initiation of dsRNA synthesis requires the presence and partial assembly of the core capsid protein. By this mechanism, the viral polymerase can carry out dsRNA synthesis only when capsid protein is available to package its newly made product. By preventing the accumulation of naked dsRNA within the cell, the virus avoids triggering dsRNA-dependent interferon signaling pathways that can induce expression and activation of antiviral host proteins.
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PMID:Coupling of rotavirus genome replication and capsid assembly. 1722 94

All pathogenic flaviviruses examined thus far inhibit host interferon (IFN) responses by suppressing the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Both Langat virus (LGTV; a member of the tick-borne encephalitis virus serogroup) and Japanese encephalitis virus use the nonstructural protein NS5 to suppress JAK-STAT signaling. However, NS5 is also critical to virus replication, contributing methyltransferase and RNA-dependent RNA polymerase (RdRP) activities. The specific amino acid residues of NS5 involved in IFN antagonism are not known. Here, we demonstrate that the LGTV NS5 JAK-STAT inhibitory domain is contained between amino acids 355 and 735 (of 903), a range which lies within the RdRP domain. Furthermore, we identified two noncontiguous stretches of specific amino acids within the RdRP, 374 to 380 and 624 to 647, as critical for inhibition of JAK-STAT signaling. Despite considerable separation on the linear NS5 sequence, these residues localized adjacent to each other when modeled on the West Nile virus RdRP crystal structure. Due to the general conservation of RdRP structures, these results suggest that the specific residues identified act cooperatively to form a unique functional site on the RdRP responsible for JAK-STAT inhibition. This insight into the mechanism underlying flavivirus IFN evasion strategies will facilitate the design of antiviral therapeutics that potentiate the action of IFN during infection.
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PMID:Identification of residues critical for the interferon antagonist function of Langat virus NS5 reveals a role for the RNA-dependent RNA polymerase domain. 1745 29

Compound A-837093, a non-nucleoside HCV RNA-dependent RNA polymerase inhibitor, displayed nanomolar potencies against HCV genotypes 1a and 1b replicons. It also exhibited an excellent metabolic profile and achieved high plasma and liver concentrations in animals. In order to characterize the development of resistance to this anti-HCV agent, HCV subgenomic 1b strain N replicon cells were cultured in the presence of A-837093 with G418. Mutations S368A, Y448H, G554D, Y555C, and D559G in the NS5B polymerase gene were identified that led to substantial decreases in the susceptibilities of 1b genotype replicons to the inhibitor A-837093. However, the resistant mutants remained susceptible to HCV protease inhibitor BILN-2061 and alpha interferon as well as to a different class of non-nucleoside HCV polymerase inhibitor. In addition, each single resistant mutation identified significantly reduced the replication capacity of mutant compared to wild-type replicon. These findings provide a strategic guide for the future development of non-nucleoside inhibitors of HCV NS5B polymerase.
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PMID:Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro. 1756 Dec 78

Chronic hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. Present treatment consists of the use of pegylated interferon plus the purine analogue ribavirin. Serious side effects and the fact that an overall 40-50% of patients do not accomplish sustained virological response with the present treatment warrant the need for novel anti-HCV therapies. The HCV serine protease and the RNA-dependent RNA polymerase have shown to be excellent targets for selective antiviral therapy. Early clinical studies have resulted in encouraging results. However, and not unexpectedly, preclinical evidence suggests that the virus may become rapidly resistant to such inhibitors. Therefore, combination therapy of drugs with different mode of action and resistance profiles may be required. This review focuses on the present status of these two families of HCV inhibitors that are in development.
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PMID:Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection. 1768 67

Cyclophilins (Cyps) are proteins that are ubiquitously present with peptidyl-prolyl cis-trans isomerase activity and play an important role in de novo protein folding and in isomerization of native proteins in several cellular systems. There is growing evidence that indicates CypB is a positive modulator of the HCV RNA-dependent RNA polymerase in the replication complex. Early in vitro and animal data with selective Cyp inhibitors show a potent anti-HCV effect. This anti-HCV effect was confirmed in the first patient study with the selective Cyp inhibitor Debio-025. Preclinical data suggest that Cyp inhibitors may present a higher barrier to the selection of resistance than protease and polymerase inhibitors and that a combination of Cyp inhibitors with either of these drugs or interferon results in additive or synergistic anti-HCV activity. By interfering at the level of host-viral interaction, Cyp inhibition may open the way for a novel approach to anti-HCV treatment that could be complementary, not only to interferon-based treatment, but also to future treatments that directly target HCV replication enzymes such as protease and polymerase inhibitors.
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PMID:Cyclophilin inhibitors in hepatitis C viral infection. 1771 21

The therapy for chronic hepatitis C (CH-C) started with interferon (IFN) monotherapy in the early 1990s and this therapy was considered effective in about 10% of cases. The present standard therapy of pegylated IFN with ribavirin achieves a sustained virologic response in about 50% of patients. However, about half of the CH-C patients are still at risk of fatal liver cirrhosis and hepatocellular carcinoma. The other significant event in hepatitis C virus (HCV) research has been the development of a cell culture system. The subgenomic replicon system enables robust HCV RNA replication in hepatoma cells. And recently, the complete life cycle of HCV has been achieved using a genotype 2a strain, JFH1. These hallmarks have provided much information about the mechanisms of HCV replication, including information on the host molecules required for the replication. Anti-HCV reagents targeting HCV proteins have been developed, and some of them are now in clinical trials. However, the RNA-dependent RNA polymerase frequently causes mutations in the HCV genome, which lead to the emergence of drug-resistant HCV mutants. Some of the cellular proteins essential for HCV RNA replication have already been discovered using the HCV cell culture system. These host molecules are also candidate targets for antivirals. Here, we describe the recent progress regarding the anti-HCV reagents targeting host metabolism.
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PMID:Modulation of host metabolism as a target of new antivirals. 1789 52

Tick-borne encephalitis virus (TBEV) NS5 protein is a multifunctional RNA-dependent RNA polymerase that is indispensable for viral replication. TBEV is considered to be highly neurovirulent and can cause lethal encephalitis. In this study, we demonstrate a novel interaction between TBEV NS5 and the PDZ protein scribble (hScrib) affecting interferon (IFN) type I and II mediated JAK-STAT signalling. The sequence of TBEV NS5 interacting with hScrib was identified using extensive site-directed mutagenesis analysis. Two consecutive mutations in the methyltransferase (MTase) domain of NS5 were found to disrupt binding to hScrib. Colocalization studies with hScrib demonstrated that TBEV NS5 was present at the plasma membrane of mammalian cells. To address the role of viral interference with the IFN response, NS5 proteins were expressed in IFN-stimulated cells. While TBEV NS5 substantially blocked phosphorylation of STAT1, a mutated NS5 protein defective in hScrib binding failed to inhibit JAK-STAT signalling correctly. Furthermore, hScrib knock-down resulted in re-localization of NS5 to intracellular locations and abrogated the impaired STAT1 phosphorylation. These results define the TBEV NS5 protein in concert with hScrib as an antagonist of the IFN response, by demonstrating a correlation between the association and JAK-STAT interference.
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PMID:Tick-borne encephalitis virus NS5 associates with membrane protein scribble and impairs interferon-stimulated JAK-STAT signalling. 1804 58

Over-expression of grouper Mx negatively regulated nodavirus activity through direct interaction, likely via the binding and perturbation of the intracellular localization of nodavirus coat protein. Deletion analysis of grouper Mx indicated that the coat protein binds to the effector domain of Mx. The presence of grouper Mx in a poly [I:C] interferon system inhibited nodavirus infection, demonstrating that grouper Mx over-expression has an inhibitory effect on both coat protein and RNA-dependent RNA polymerase of nodavirus antigens, which results in reduced viral yields. We conclude that grouper Mx has a key role in cellular resistance to nodavirus infection.
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PMID:Grouper Mx confers resistance to nodavirus and interacts with coat protein. 1822 39


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