Abstract：
:The hepatitis C virus (HCV) NS3 protein contains a serine proteinase domain implicated in the maturation of the viral polyprotein. NS3 forms a stable heterodimer with NS4A, a viral membrane protein that acts as an activator of the NS3 proteinase. The three-dimensional structure of the NS3 proteinase complexed with an NS4A-derived peptide has been determined. The NS3 proteinase adopts a chymotrypsin-like fold. A beta-strand contributed by NS4A is clamped between two beta-strands within the N terminus of NS3. Consistent with the requirement for extraordinarily long peptide substrates (P6-P4'), the structure of the NS3 proteinase reveals a very long, solvent-exposed substrate-binding site. The primary specificity pocket of the enzyme is shallow and closed at its bottom by Phe-154, explaining the preference of the NS3 proteinase for cysteine residues in the substrate P1 position. Another important feature of the NS3 proteinase is the presence of a tetrahedral zinc-binding site formed by residues Cys-97, Cys-99, Cys-145 and His-149. The zinc-binding site has a role in maintaining the structural stability and guiding the folding of the NS3 serine proteinase domain. Inhibition of the NS3 proteinase activity is regarded as a promising strategy to control the disease caused by HCV. Remarkably, the NS3 proteinase is susceptible to inhibition by the N-terminal cleavage products of substrate peptides corresponding to the NS4A/NS4B, NS4B/NS5A and NS5A/NS5B cleavage sites. The Ki values of the inhibitory products are lower than the K(m) values of the respective substrates and follow the order NS4A < NS5A < NS4B. Starting from the observation that the NS3 proteinase undergoes product inhibition, very potent, active site-directed inhibitors have been generated using a combinatorial peptide chemistry approach.
journal_name
Antivir Therjournal_title
Antiviral therapyauthors
De Francesco R,Pessi A,Steinkühler Csubject
Has Abstractpub_date
1998-01-01 00:00:00pages
99-109issue
Suppl 3eissn
1359-6535issn
2040-2058journal_volume
3pub_type
杂志文章,评审abstract：BACKGROUND:ITX 5061 is a highly potent small molecule inhibitor of scavenger receptor-B1, an integral transmembrane protein that is found in liver cells and is actively involved in the transport of HCV into hepatocytes. Currently, ITX 5061 is being investigated in monoinfected hepatitis C patients in a proof-of-concept...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP2354
更新日期：2013-01-01 00:00:00
abstract：:Compounds that can block the CXCR4 chemokine receptor are a promising new class of antiretroviral agents. In these experiments we studied the effect of a modified form of the native stromal cell-derived factor-1 (SDF-1), Met-SDF-1beta. The in vitro susceptibility of two different CXCR4-tropic HIV-1 strains was determi...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：
更新日期：2000-09-01 00:00:00
abstract：BACKGROUND:Two distinct inhibitors of the HCV protease have been approved for the treatment of patients infected with HCV genotype-1. These drugs are highly efficient in suppressing HCV replication; however, their use is limited by the emergence of viral mutants resistant to them after a very short time of treatment. B...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP2326
更新日期：2013-01-01 00:00:00
abstract：BACKGROUND:Zidovudine (3'-azido-3'-deoxythymidine, AZT), administered to pregnant women alone or in combination with other antiretroviral drugs, greatly reduces the mother-to-child transmission of HIV-1. The potential genotoxicity of these molecules is underestimated and wide-ranging evaluation of its biological and cl...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：
更新日期：2007-01-01 00:00:00
abstract：:Infection with influenza viruses, including seasonal, avian and pandemic viruses, remains a worldwide public health problem. Although influenza virus infection is both vaccine preventable and drug treatable, high rates of mutation and reassortment of viruses can result in reduced effectiveness of vaccines or drugs. Cu...
journal_title：Antiviral therapy
pub_type： 杂志文章,评审
doi：10.3851/IMP2067
更新日期：2012-01-01 00:00:00
abstract：BACKGROUND:Rilpivirine-based regimens are now preferred or alternative first-line regimens according to many HIV treatment guidelines. Recently, a surveillance study conducted in Argentina determined that prevalence of pretreatment resistance to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) ...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP3147
更新日期：2017-01-01 00:00:00
abstract：BACKGROUND:In HIV-infected patients, therapeutic drug monitoring (TDM) of antiretroviral drugs is recommended in special populations and in specific situations to optimize therapy. Currently, TDM is performed via measurement of drug plasma concentrations; however, dried blood spots (DBS) may offer a patient friendly an...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP2501
更新日期：2013-01-01 00:00:00
abstract：BACKGROUND:Lamivudine (3TC) therapy can cause the emergence of M1841/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M1841/V in patients receiving combination a...
journal_title：Antiviral therapy
pub_type： 杂志文章,随机对照试验
doi：
更新日期：2006-01-01 00:00:00
abstract：BACKGROUND:Hepatitis delta virus (HDV) infection therapy is unclear. This systematic analysis aimed to clarify the evidence on the efficacy of interferon (IFN)-α-based therapy in HDV. METHODS:We performed a systematic search on electronic databases including MEDLINE (1970 to January 2011), Web of Science, The Cochrane...
journal_title：Antiviral therapy
pub_type： 杂志文章,评审
doi：10.3851/IMP2306
更新日期：2012-01-01 00:00:00
abstract：BACKGROUND:The increased risk for cardiovascular disease (CVD) in HIV is well established. Despite high prevalence of viral hepatitis coinfection with HIV, there are few studies on the risk of CVD amongst antiretroviral therapy (ART)-treated coinfected patients. METHODS:Ontario HIV Treatment Network Cohort Study parti...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP2724
更新日期：2014-01-01 00:00:00
abstract：BACKGROUND:Hepatitis C virus genotype 1B responds poorly to treatment with interferon, in contrast to the more interferon-sensitive genotypes 2 and 3. Studies on combination therapy regimens with PEG-interferon and ribavirin report sustained response rates that generally do not exceed 50%, in contrast to sustained resp...
journal_title：Antiviral therapy
pub_type： 杂志文章,meta分析
doi：
更新日期：2004-04-01 00:00:00
abstract：OBJECTIVE:To assess the impact of nucleoside analogue reverse transcriptase inhibitor (NRTI) combination therapy on muscle and liver lactate metabolism in HIV-infected patients. METHODS:This cross-sectional study involved HIV-infected patients who were either antiretroviral-naive (Group 1) or were receiving either a s...
journal_title：Antiviral therapy
pub_type： 杂志文章,多中心研究
doi：
更新日期：2005-01-01 00:00:00
abstract：BACKGROUND:Anaemia has been linked with mortality in HIV infection. The mechanism of anaemia in the era of contemporary antiretroviral therapy is not understood. The aim of this study was to describe the association between anaemia and markers of immune activation and inflammation in a cohort of HIV-infected adults on ...
journal_title：Antiviral therapy
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.3851/IMP2940
更新日期：2015-01-01 00:00:00
abstract：:The effectiveness of current antiretroviral therapies has led to more patients receiving long-term therapy, and increasing numbers of older patients. The complex interactions between HIV infection, ageing, comorbid conditions and drug-related toxicities, and their combined effects on patient health and quality of life...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP1470
更新日期：2009-01-01 00:00:00
abstract：:With the advent of the human immunodeficiency virus (HIV) protease inhibitors and the non-nucleoside reverse transcriptase inhibitors, the importance of drug-drug interactions with antiretroviral agents is becoming increasingly recognized. Every clinician involved in the care of HIV-infected persons should have a broa...
journal_title：Antiviral therapy
pub_type： 杂志文章,评审
doi：
更新日期：1997-07-01 00:00:00
abstract：:We investigated whether or not mutations at codon 215 in the HIV reverse-transcriptase-encoding gene predicted a lower efficacy of didanosine therapy, as defined by survival of patients and change in CD4 cell counts in 121 HIV-infected, zidovudine-experienced patients. A trend for shorter survival, although not reachi...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：
更新日期：1996-08-01 00:00:00
abstract：:HIV drug resistance remains one of the most important influences on long-term therapeutic prospects. Resistance and therapeutic failure arises out of the selection and preservation of randomly generated genomic mutations that confer a replicative advantage in the presence of one or more antiretrovirals. The primary co...
journal_title：Antiviral therapy
pub_type： 杂志文章,评审
doi：
更新日期：2001-01-01 00:00:00
abstract：BACKGROUND:Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir. METHODS:Cro...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP2411
更新日期：2012-01-01 00:00:00
abstract：BACKGROUND:The tuberculosis (TB) mortality rate of registered TB patients in Malawi is 23%, and 59% of the deaths occur in the first 2 months of treatment. HIV-related complications appear to be an important cause. Starting antiretroviral therapy early during tuberculosis treatment may improve outcome but problems ofte...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：
更新日期：2007-01-01 00:00:00
abstract：:MicroRNAs regulate gene expression by binding to the 3'-untranslated region (UTR) of target messenger RNAs (mRNAs). The importance of microRNAs has been shown for several liver diseases, for example, viral hepatitis. MicroRNA-122 is highly abundant in the liver and is involved in the regulation of lipid metabolism. Mi...
journal_title：Antiviral therapy
pub_type： 杂志文章,评审
doi：10.3851/IMP2766
更新日期：2014-01-01 00:00:00
abstract：BACKGROUND:There are few published data characterizing patterns of liver stiffness measurements (LSMs) among HCV-infected persons and their potential impact on clinical decisions (for example, deferring treatment and hepatocellular carcinoma surveillance). METHODS:A total of 591 HCV-infected injection drug users in a ...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP2085
更新日期：2012-01-01 00:00:00
abstract：:Although zidovudine (ZDV) is effective in HIV-1-infected patients, the duration of its efficacy may be short when treatment is started in advanced HIV disease. This pilot prospective case-control study was designed to evaluate the combination of ZDV plus didanosine [ddI] compared with ZDV monotherapy as an initial the...
journal_title：Antiviral therapy
pub_type： 临床试验,杂志文章
doi：
更新日期：1996-04-01 00:00:00
abstract：BACKGROUND:The World Health Organization recommends HBV-HIV-coinfected individuals start antiretroviral therapy containing tenofovir. Here we describe first-line tenofovir use and treatment outcomes in coinfected patients in Asia. METHODS:HBV surface antigen positive patients enrolled in the TREAT Asia HIV Observation...
journal_title：Antiviral therapy
pub_type： 杂志文章,多中心研究
doi：10.3851/IMP2972
更新日期：2016-01-01 00:00:00
abstract：BACKGROUND:Insulin resistance (IR) was one of the first reported complications in HIV-positive patients who were receiving antiretroviral therapy (ART). However, the metabolic effects of newer fixed-dose ART combinations are unclear. METHODS:This Phase I prospective randomized open-label study evaluated the effects on...
journal_title：Antiviral therapy
pub_type： 杂志文章,随机对照试验
doi：10.3851/IMP3049
更新日期：2016-01-01 00:00:00
abstract：BACKGROUND:A genome-wide association study revealed an association between variants of the inosine triphosphatase (ITPA) gene and ribavirin (RBV)-induced anaemia. The aim of this study was to replicate this finding in an independent Japanese cohort and to define a method to allow pretreatment prediction of anaemia in c...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP1796
更新日期：2011-01-01 00:00:00
abstract：BACKGROUND:Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lam...
journal_title：Antiviral therapy
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.3851/IMP1931
更新日期：2011-01-01 00:00:00
abstract：BACKGROUND:Recently, we identified increased rates of CD4(+) T-cell apoptosis in HCV-infected HIV-positive patients as a potential mechanism for enhanced mortality in patients with HIV/HCV coinfection. Since this effect might be attributed to changes in receptor-induced apoptosis, we studied expression and function of ...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：10.3851/IMP1882
更新日期：2011-01-01 00:00:00
abstract：:Zidovudine treatment of human immunodeficiency virus (HIV) infection induces drug-resistant viral strains harbouring specific amino acid substitutions in the reverse transcriptase (RT). To investigate whether this phenomenon could be observed in the case of human T lymphotropic virus type I (HTLV-I) infection, we anal...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：
更新日期：1997-04-01 00:00:00
abstract：BACKGROUND:Antibodies to liver-kidney microsome type 1 (anti-LKM-1), which are a marker of autoimmune hepatitis, are found in a minority of patients with chronic hepatitis C virus (HCV) infection. Whether interferon/ribavirin therapy is safe and effective in these patients is unclear. AIM:To describe the prevalence, c...
journal_title：Antiviral therapy
pub_type： 临床试验,杂志文章
doi：
更新日期：2005-01-01 00:00:00
abstract：BACKGROUND/AIMS:We conducted a case-control study to investigate the efficacy of interferon-alpha (IFN-alpha) and ribavirin combination therapy for patients with chronic hepatitis C and B virus (HCV/HBV) coinfection and to elucidate the interaction of these two viruses. METHODS:Forty-two chronic HCV/HBV-coinfected pat...
journal_title：Antiviral therapy
pub_type： 杂志文章
doi：
更新日期：2005-01-01 00:00:00
