Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0023890 (cirrhosis)
42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) causes chronic hepatitis, which often results in the development of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. In this study, we demonstrated that the non-structural protein NS3 of HCV enhances cyclooxygenase-2 (COX-2) gene promoter activity, COX-2 mRNA expression, COX-2 protein production, and prostaglandin E2 (PGE2) release in HepG2 cells in a concentration-dependent fashion. We also showed that transcription factor NF-kappaB is required for the activation of COX-2 regulated by NS3. In addition, multiple signaling pathways are involved cooperatively in the expression of COX-2 activated by the viral protein in a calcium-independent manner, which requires signaling components including JNK, ERK, and PKD2. A thorough investigation of mechanism involved in the activation of COX-2 regulated by HCV would provide insights into our understanding the processes of liver inflammatory response and hepatocellular carcinoma development caused by the viral infection and also into the development of novel therapeutics against HCV infection.
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PMID:NS3 protein of hepatitis C virus regulates cyclooxygenase-2 expression through multiple signaling pathways. 1796 30

Hepatitis C virus (HCV) is a major cause of chronic hepatitis that can lead to cirrhosis and hepatocellular carcinoma. To study the effects of HCV protein expression on host cells, we established conditional expression of the full-length open reading frame (ORF) of an infectious cDNA clone of HCV (genotype 1a, H77 strain) in the nontransformed human hepatocyte line cell HH4 using the ecdysone receptor regulatory system. Treatment with the ecdysone analog ponasterone-A induced tightly regulated and dose-dependent full-length HCV ORF expression and properly processed HCV proteins. HCV Core, NS3, and NS5A colocalized in perinuclear regions and associated with the early endosomal protein EEA1. HCV ORF expression caused marked growth inhibition, increased intracellular reactive oxygen species, up-regulation of glutamate-l-cysteine ligase activity, increased glutathione level, and activation of nuclear factor kappaB. Although it was not directly cytotoxic, HCV ORF expression sensitized HH4 cells to Fas at certain concentrations but not to tumor necrosis factor-related apoptosis-inducing ligand. HCV ORF expression in HH4 cells up-regulated genes involved in innate immune response/inflammation and oxidative stress responses and down-regulated cell growth-related genes. Expression of HCV ORF in host cells may contribute to HCV pathogenesis by producing oxidative stress and increasing the expression of genes related to the innate immune response and inflammation.
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PMID:Responses of nontransformed human hepatocytes to conditional expression of full-length hepatitis C virus open reading frame. 1799 16

More than 170 million people worldwide are affected by the hepatitis C virus (HCV). The disease has been described as a "silent epidemic" and "a serious global health crisis". HCV infection is a leading cause of chronic liver disease such as cirrhosis, carcinoma, or liver failure. The current pegylated interferon and ribavirin combination therapy is effective in only 50% of patients. Its moderate efficacy and apparent side effects underscore the need for safer and more effective treatments. The nonstructural NS3 protease of the virus plays a vital role in the replication of the HCV virus. The development of small molecule inhibitors of NS3 protease as antiviral agents has been intensively pursued as a viable strategy to eradicate HCV infection. However, it is a daunting task. The protease has a shallow and solvent-exposed substrate binding region, and the inhibitor binding energy is mainly derived from weak lipophilic and electrostatic interactions. Moreover, lack of a robust in vitro cell culture system and the absence of a convenient small animal model have hampered the assessment of both in vitro and in vivo efficacy of any antiviral compounds. Despite the tremendous challenges, with access to a recently developed cell-based replicon system, major progress has been made toward a more effective small molecule HCV drug. In our HCV program, facing no leads from our screening effort, a structure-based drug design approach was carried out. An alpha-ketoamide-type electrofile was designed to trap the serine hydroxyl of the protease. Early ketoamide inhibitors mimicked the structures of the peptide substrates. With the aid of X-ray structures, we successfully truncated the undecapeptide lead that had a molecular weight of 1265 Da stepwise to a tripeptide with a molecular weight of 500 Da. In an attempt to depeptidize the inhibitors, various strategies such as hydrazine urea replacement of amide bonds and P2 to P4 and P1 to P3 macrocyclizations were examined. Further optimization of the tripeptide inhibitors led to the identification of the best moieties for each site: primary ketoamide at P', cyclobutylalanine at P1, gem-dimethylcyclopropylproline at P2, tert-leucine at P3, and tert-butyl urea as capping agent. The combination of these led to the discovery of compound 8 (SCH 503034, boceprevir), our clinical candidate. It is a potent inhibitor in both enzyme assay (Ki* = 14 nM) and cell-based replicon assay (EC 90 = 0.35 microM). It is highly selective (2200x) against human neutrophil elastase (HNE). Boceprevir is well tolerated in humans and demonstrated antiviral activity in phase I clinical trials. It is currently in phase II trials. This Account details the complexity and challenges encountered in the drug discovery process.
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PMID:Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. 1819 21

Hepatitis C virus (HCV) infection is the major etiological agent of chronic hepatitis, which leads to liver cirrhosis and hepatocellular carcinomas. HCV NS3 helicase is a promising target of anti-virus therapy. In this report, we discuss a strategy to generate monoclonal antibodies (MAbs) of the HCV NS3 helicase, and investigate its potential characteristic. Our results showed the production of MAbs against NS3 helicase, which could specifically recognize the native NS3 helicase in transiently transfected cells in the immunofluorescence experiment. The resultant MAbs were used as the first antibody in Western blot analyses, and observed the specific band that defines the NS3 helicase. Likewise, one MAb could inhibit the NS3 helicase enzymatic activity distinctly in the NS3 helicase-mediated DNA-unwinding assay. To conclude, these antibodies may be useful to generate specific diagnostic tools for HCV infection and may also be developed for potential therapeutics.
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PMID:Production and characterization of monoclonal antibody specific for NS3 helicase of hepatitis C virus. 1858 11

Chronic hepatitis C infection is the leading causes for cirrhosis of the liver and hepatocellular carcinoma, leading to liver failure and liver transplantation. The etiological agent, HCV virus produces a single positive strand of RNA that is processed with the help of serine protease NS3 to produce mature virus. Inhibition of NS3 protease can be potentially used to develop effective drugs for HCV infections. Numerous efforts are now underway to develop potent inhibitors of HCV protease that contain ketoamides as serine traps. Herein we report the synthesis of a series of potent inhibitors that contain a boronic acid as a serine trap. The activity of these compounds were optimized to 200pM. X-ray structure of compound 17 bound to NS3 protease is also discussed.
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PMID:Potent inhibitors of HCV-NS3 protease derived from boronic acids. 1902 70

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P(1)-P(3) macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P(3) imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.
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PMID:Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C virus NS3 protease. 1910 54

HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, we present the P1-P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential backup candidates to our first generation drug candidate, Sch 503034 (1). Different P1-P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of l-serine derived macrocycle 32 (Ki* = 3 nM, EC90 = 30 nM) and allo-threonine derived macrocycle 36 (Ki* = 3 nM, EC90 = 30 nM) as potent HCV NS3 protease inhibitors.
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PMID:Design, synthesis, and evaluation of oxygen-containing macrocyclic peptidomimetics as inhibitors of HCV NS3 protease. 1915 50

Chronic hepatitis C affects 130,000,000 people worldwide. Hepatitis C virus (HCV) is a single-strand RNA virus responsible for most cases of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) in the Western world. The gold standard for the treatment of chronic hepatitis C (combination of pegylated-interferon alpha and ribavirin) results in a sustained virological response (namely, clearance of serum HCV RNA 6 months after therapy withdrawal) in only about half treated patients. Therefore, there is a race to develop new drugs for the treatment of HCV infection. One of the most promising approaches is to use protease inhibitors, i.e. drugs inhibiting NS3/NS4A HCV protease, which plays a crucial role in the viral life cycle. Telaprevir (VX-950) is the protease inhibitor in the most advanced phase of clinical testing. Telaprevir is orally available and when used in monotherapy it induced a median decline of 4 logs of HCV RNA after two weeks of therapy. However, mutants with a lower sensitivity to telaprevir have been demonstrated in a high proportion of patients within 14 days of monotherapy. The drug has been used in clinical trials in combination with pegylated-interferon and ribavirin. This triple combination resulted in a higher rate of SVR but also in a higher rate of side effects (rash, gastrointestinal disorders, and anemia) than standard treatment. This review focuses on the mechanism of action, pharmacokinetics, clinical efficacy, and tolerability of telaprevir, and on possible use of this drug in combination with other drugs for the treatment of HCV infection.
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PMID:Telaprevir: a promising protease inhibitor for the treatment of hepatitis C virus infection. 1927 15

Chronic infection with hepatitis C virus (HCV) affects 130 million people worldwide and is a major cause of liver cirrhosis and liver cancer. After translation of the HCV RNA genome into a polyprotein, 2 viral proteases process its non-structural protein (NS) region. While the essential chymotrypsin-like serine protease NS3-4A mediates all cleavages downstream of NS3, the NS2-3 cysteine protease catalyzes a vital cleavage at the NS2/3 site. Protease activity of NS2-3 has been described to require, besides NS2, the N-terminal 181 aa of NS3. The latter domain corresponds to the NS3 serine protease domain and contains a structural Zn(2+)-binding site with functional importance for both viral proteases. The catalytic triad of the NS2-3 protease resides in NS2; the role of the NS3 part in proteolysis remained largely undefined. Here we report a basal proteolytic activity for NS2 followed by only 2 amino acids of NS3. Basal activity could be dramatically enhanced by the NS3 Zn(2+)-binding domain (NS3 amino acids 81-213) not only in cis but also in trans which, however, required a more extended N-terminal part of NS3 downstream of NS2 in cis. Thus, this study defines for the first time (i) NS2 as a bona fide protease, (ii) NS3 as its regulatory cofactor, and (iii) functional subdomains in NS3 that cooperate in NS2 protease activation. These findings give new mechanistic insights into function and regulation of the NS2 protease and have important implications for the development of anti-HCV therapeutics.
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PMID:Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3. 1928 77

Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.
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PMID:Toward second generation hepatitis C virus NS3 serine protease inhibitors: discovery of novel P4 modified analogues with improved potency and pharmacokinetic profile. 1937 Oct 95


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