Xia & He Publishing

Review Article Open Access

The Discovery and Development of Boceprevir: A Novel, First‐generation Inhibitor of the Hepatitis C Virus NS3/4A Serine Protease

Anita Y. M. Howe, Srikanth Venkatraman

Published online September 28, 2013

[ Html ] [ PDF ] [ Google Scholar ] [ Cite ]

Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2013.002XX

Abstract

An estimated 2–3% of the world's population is infected with hepatitis C virus (HCV), making it a major global health problem. Consequently, over the past 15 years, there has been [...] Read more.

An estimated 2–3% of the world's population is infected with hepatitis C virus (HCV), making it a major global health problem. Consequently, over the past 15 years, there has been a concerted effort to understand the pathophysiology of HCV infection and the molecular virology of replication, and to utilize this knowledge for the development of more effective treatments. The virally encoded non-structural serine protease (NS3) is required to process the HCV polyprotein and release the individual proteins that form the viral RNA replication machinery. Given its critical role in the replication of HCV, the NS3 protease has been recognized as a potential drug target for the development of selective HCV therapies. In this review, we describe the key scientific discoveries that led to the approval of boceprevir, a first-generation, selective, small molecule inhibitor of the NS3 protease. We highlight the early studies that reported the crystal structure of the NS3 protease, its role in the processing of the HCV polyprotein, and the structural requirements critical for substrate cleavage. We also consider the novel attributes of the NS3 protease-binding pocket that challenged development of small molecule inhibitors, and the studies that ultimately yielded milligram quantities of this enzyme in a soluble, tractable form suitable for inhibitor screening programs. Finally, we describe the discovery of boceprevir, from the early chemistry studies, through the development of high-throughput assays, to the phase III clinical development program that ultimately provided the basis for approval of this drug. This latest phase in the development of boceprevir represents the culmination of a major global effort to understand the pathophysiology of HCV and develop small molecule inhibitors for the NS3 protease.

Full article

Review Article Open Access

Genome‐Wide Association Study Reveals Host Genetic Factors for Liver Diseases

Nao Nishida, Katsushi Tokunaga, Masashi Mizokami

Published online September 28, 2013

[ Html ] [ PDF ] [ Google Scholar ] [ Cite ]

Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2013.010XX

Abstract

A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide [...] Read more.

A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide single-nucleotide polymorphism typing technologies, which are now commercially available, accompanied by statistical methods to identify host genetic factors that are associated with target diseases or complex genetic traits. One of the most striking features of the GWAS strategy is the ability to identify unexpected disease-associated genetic markers across the entire human genome. Here, we describe the technological aspects of the GWAS strategy with examples from actual GWAS reports related to hepatitis research, including drug response for patients with chronic hepatitis C, susceptibility to primary biliary cirrhosis, and hepatitis-B-related hepatocellular carcinoma.

Full article

Review Article Open Access

The Discovery and Development of a Potent Antiviral Drug, Entecavir, for the Treatment of Chronic Hepatitis B

Hong Tang, Jamie Griffin, Steven Innaimo, Lois Lehman-Mckeeman, Cyril Llamoso

Published online September 28, 2013

[ Html ] [ PDF ] [ Google Scholar ] [ Cite ]

Journal of Clinical and Translational Hepatology. doi:10.14218/JCTH.2013.00006

Abstract

Since the first approval of interferon for the treatment of chronic hepatitis B virus (HBV) infection in 1992, six additional antivirals have been developed: pegylated interferon-alfa2a, [...] Read more.

Since the first approval of interferon for the treatment of chronic hepatitis B virus (HBV) infection in 1992, six additional antivirals have been developed: pegylated interferon-alfa2a, and the oral antivirals lamivudine, adefovir, telbivudine, entecavir and tenofovir. The availability of animal models for HBV infection and hepatocyte cell culture led to the discovery and development of oral antivirals targeted at HBV polymerase and reverse transcriptase, which inhibit viral replication. The discovery and development of entecavir, the first oral anti-HBV drug with both potent antiviral activity and a high genetic barrier to resistance, took more than 10 years before it was first approved in the USA. Since then, multiple real-life studies have provided data consistent with the findings of the registration trials and the long-term rollover study in terms of efficacy, resistance, and safety. Data from the long-term follow-up of patients enrolled in the registration studies showed that treatment with entecavir can lead to significant improvements in liver histopathology, and recent cohort studies have demonstrated that treatment with entecavir may reduce disease progression and the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. In addition, real-life studies suggest that entecavir may reduce HCC recurrence and increase survival rates in patients with HBV-related HCC post-surgical resection.

Full article

Research Article Open Access

Statins Cause Profound Effects on Gene Expression in Human Cancer Cells In Vitro: The Role of Membrane Microdomains

David John Garnett, Trevor James Greenhough

Published online May 1, 2013