Recent advances in prevention and treatment of hepatitis C virus infections

Wang, Q. May; Heinz, Beverly A.

doi:10.1007/978-3-0348-7784-8_3

Cited by 16 publications

(23 citation statements)

References 117 publications

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“…Approximately 70% of the acute infections may progress to a chronic state, which, if untreated, can lead to cirrhosis and liver failure, or hepatocellular carcinoma in 10 -20 years [4]. To date, neither a protective vaccine against HCV nor an effective therapy with an acceptable broad spectrum of action against all genotypes of HCV is available [3]. The current standard of care for the treatment of chronic HCV infection consists of the combined use of pegylated interferon-(PEG-IFN-) and the nucleoside analogue ribavirin (RBV), which is genotype specific and less than 50% of individuals who are infected with genotype 1 (the most common worldwide) obtain a sustained virological response, and is often associated with significant side effects including flu-like symptoms, depression and anemia [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…With ~ 200 million people infected worldwide (3% of the world population) and an insufficient current standard of care, prevalent infection with hepatitis C virus (HCV) which was first identified in 1989 as the etiological agent of parenteral non-A and non-B hepatitis, remains a global health concern with 3 -4 million individuals being newly infected every year [1][2][3]. Approximately 70% of the acute infections may progress to a chronic state, which, if untreated, can lead to cirrhosis and liver failure, or hepatocellular carcinoma in 10 -20 years [4].…”

Section: Introductionmentioning

confidence: 99%

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Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Zhang

Li²,

Wang³

et al. 2011

CMC

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Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Zhang

Li²,

Wang³

et al. 2011

CMC

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“…Of the estimated 200 million cases of HCV infection that exist worldwide, over 4.1 million infections occur in the United States alone [5]. At present, neither a vaccine against HCV nor an effective therapy with acceptable broad spectrum of action against all genotypes of HCV are available [6,7]. A currently approved HCV therapy, in the form of pegylated interferon (PEG-IFN-), either alone or in combination with ribavirin, a broad spectrum anti-viral agent, has found limited patient compliance because of the severe side-effects associated with these drugs [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…This protein is processed by host and viral proteases into four structural (Core, E1, E2, and p7) and six nonstructural (NS) proteins (NS2, -3, -4A, -4B, -5A, and -5B) [11,12]. NS5B a 66 kDa RNA-dependent RNA polymerase (RdRp) has attracted the attention of medicinal chemists as a target for drug development since it plays a pivotal role in HCV replication and its counterpart is lacking in the host [10,13]. As a result of high throughput screening (HTS) work by pharmaceutical companies several *Address correspondence to this author at the Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439; Tel: (718)-990-5405; Fax: (718)-990-1877; E-mail: talelet@stjohns.edu chemotypes have been identified as nonnucleoside inhibitors (NNIs) of NS5B polymerase.…”

Section: Introductionmentioning

confidence: 99%

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

Talele

2008

CBC

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Infections caused by hepatitis C virus (HCV) are a significant worldwide health problem for which novel therapies are urgently needed. One attractive and viable therapeutic target is HCV NS5B RNA-dependent RNA polymerase (RdRp) since it is essential for the replication of the viral genome of HCV. The hunt for nonnucleoside inhibitors (NNIs) of HCV NS5B polymerase has led to the identification of several allosteric pockets. However, because the topographical features of these binding sites vary across and even within diverse HCV genotypes, the discovery of new antiviral drugs capable of inhibiting HCV RdRp in the face of variable binding pockets becomes a challenging endeavor. This review focuses on recent accomplishments in the development of new NNIs of HCV NS5B polymerase and on their binding mechanisms to the respective allosteric pockets. Potential difficulties surrounding the discovery of future NNIs targeted to different allosteric pockets of HCV NS5B and to HCV NS5B from different genotypes are also discussed.

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“…Although it is estimated that 200 million cases of HCV infections exist worldwide at present neither a vaccine nor an effective therapy with broad spectrum mode of action is so far available [3]. Currently the anti-HCV therapy is based primarily on the prescription of interferon-(IFN) alone or in combination with the nucleoside inhibitor ribavirin (RBV) [4]. Due to low therapeutic effects and associated side effects of these strategies, such as depression and anemia, the development of more effective and safer anti-HCV agents has become an imperative necessity.…”

Section: Introductionmentioning

confidence: 99%

Ligand and Structure Based Virtual Screening Strategies for Hit-Finding and Optimization of Hepatitis C Virus (HCV) Inhibitors

Melagraki¹,

Afantitis

2011

CMC

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Virtual Screening (VS) has experienced increased attention into the recent years due to the large datasets made available, the development of advanced VS techniques and the encouraging fact that VS has contributed to the discovery of several compounds that have either reached the market or entered clinical trials. Hepatitis C Virus (HCV) nonstructural protein 5B (NS5B) has become an attractive target for the development of antiviral drugs and many small molecules have been explored as possible HCV NS5B inhibitors. In parallel with experimental practices, VS can serve as a valuable tool in the identification of novel effective inhibitors. Different techniques and workflows have been reported in literature with the goal to prioritize possible potent hits. In this context, different virtual screening strategies have been deployed for the identification of novel Hepatitis C Virus (HCV) inhibitors. This work reviews recent applications of virtual screening in an effort to identify novel potent HCV inhibitors.

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Recent advances in prevention and treatment of hepatitis C virus infections

Cited by 16 publications

References 117 publications

Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

Ligand and Structure Based Virtual Screening Strategies for Hit-Finding and Optimization of Hepatitis C Virus (HCV) Inhibitors

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