Hepatitis C: Antiviral Drug Discovery and Development
"highly recommended" (Aus. J. Med. Sci.)
"a thorough review" (Doodys)
"in-depth information" (Microbiol. Today)
Caister Academic Press
Seng-Lai Tan and Yupeng He
Hoffman-La Roche Inc., Nutley, NJ, USA and Antiviral Research, Abbott Laboratories, Abbott Park, IL 60064, USA (respectively)
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The hepatitis C virus (HCV) is a significant public health problem of international importance. HCV is capable of establishing chronic infections resulting in progressive liver damage and other problems. Current drug therapies are ineffective highlighting the need for better antiviral drugs. Recent research in HCV genetics and molecular biology have led to significant advances in our understanding of the life cycle of this important pathogen and may ultimately lead to better antiviral strategies.
The editors of this book have recruited experts from around the world to produce a timely and well-compiled review of current HCV research with an emphasis on antiviral drug development. The chapters provide in-depth reviews of the most critical areas of research. Topics covered include: the HCV life cycle, HCV assays, HCV resources, HCV databases, HCV infection systems, models of hepatitis C infections, overview of the drug pipeline, clinical trial design, clinical virology and drug development, NS3 protease inhibitors, NS3-NS4A complex inhibitors, NS3 helicase inhibitors, NS4B targets and inhibitors, NS5A inhibitors, nucleoside inhibitors, NS5B polymerase inhibitors, glycoprotein-dependent entry, host cell targets and inhibitors, and innate immunity for HCV antiviral therapy.
An essential book for scientists involved with HCV and anyone interested in antiviral drug development. A recommended text for all virology libraries.
"a thorough review ... a valuable book for scientists and drug development companies searching for a permanent cure for HCV." from Doodys
"This is an ambitious and broad-ranging volume that provides a comprehensive, detailed and accurate account of the current situation in the search for new antiviral agents to treat hepatitis C virus infection. It has been written by an impressive array of the leading researchers in the field and consequently it provides in-depth information about all the direct-acting antivirals that are currently under development, as well as those targeted to host cell factors." from Microbiology Today
"A major appeal ... is the inclusion of scores of diagrams, illustrations and tables. The volume is comprehensively referenced and includes an extensive bibliography ... will appeal to and be a valuable resource to all healthcare workers in the field of hepatitis serology, particularly for medical scientists and researchers. It is highly recommended." from Australian Journal of Medical Science (2014) 35(1): 37-38.
Table of contents
1. An Overview of the Hepatitis C Virus Life Cycle
Timothy L. Tellinghuisen
The hepatitis C virus (HCV) is a significant public health problem of international scope. HCV is capable of establishing chronic infections in the majority of those infected, resulting in progressive liver damage and a host of extra-hepatic disorders. Current drug therapies are ineffective in clearing infections from the majority of patients, highlighting the need for better anti-viral drugs. Recent developments in HCV genetic systems have led to significant advances in our understanding of the life cycle of this important pathogen, and it is this understanding that will ultimately lead to better anti-viral strategies. It is the purpose of this chapter to provide an overview of the life cycle of HCV, with a focus on aspects of the viral life cycle that might be amenable to future drug therapies.
2. Hepatitis C Virus Related Assays
Zhuhui Huang, Zhaohui Cai and Michael G. Murray
Development of appropriate assays and model systems in Hepatitis C virus (HCV) research has been critical to the initial discovery of the etiological agent as well as having been integral to the discovery and development of antiviral therapies over the years that followed. The vast amount of protein structural data that has been developed greatly facilitated and guided the chemistry of antiviral development. Meanwhile, various cell-based assays have been developed to further enhance our understanding of HCV virology and virus-host interactions, and to be used for development of potential therapeutics for intervention. In this chapter, we will highlight various cell-based assays and biochemical assays based on purified proteins in well characterized buffer systems, made possible through molecular virology.
3. Public HCV Resources
Deborah R. Taylor
The tremendous progress in the field of HCV research has led to an explosion of resources, ranging from research tools and scientific reagents to information sources, including internet tools, meetings and conferences, and regulation policies. Access to such valuable HCV resources is important to facilitate HCV pathogenesis research as well as drug discovery and development This chapter summarizes the current major resources that are publicly available for scientists, physicians, health professionals, educators, and patients.
4. HCV Databases
Carla Kuiken and Richard Scheuermann
Sequence databases provide a resource for scientific researchers worldwide that is especially important for highly variably pathogens such as HCV. There are currently a number of HCV sequence databases, two of which will be discussed in detail in this review. The Los Alamos HCV sequence database has been widely used since 2004, and still is a commonly used resource. A new addition is the Virus Pathogen Resource, which contains sequences from viral pathogens from many different families, and does not focus on HCV. We compare mission, features, and future plans of both databases and attempt to provide some guidance to help users decide which resource is more useful for specific data analysis problems.
5. HCV Infection Systems
Hepatitis C virus (HCV) infection causes chronic liver disease and is a health problem worldwide. Recent rapid progress in HCV research has been largely dependent on the development of an HCV culture system and infectious small animal model. The most important part of the HCV infection system is the discovery of the JFH-1 clone isolated from a fulminant hepatitis C patient. The JFH-1strain fits into the cluster of genotype 2a, and its viral genome sequence is monoclonal. The JFH-1 strain replicates efficiently in cultured cell lines without acquiring adaptive mutations, and it secretes infectious viral particles into culture medium. This infectious HCV system provides for the first time a powerful tool to study the viral life cycle, construct anti-viral strategies and develop effective vaccines.
6. The Chimpanzee Model of Hepatitis C Infections and Small Animal Surrogates
Robert E. Lanford, Stanley M. Lemon and Christopher Walker
The chimpanzee model of HCV infection has been instrumental in many of the key advances in HCV research and therapy. The demonstration of an infectious agent for NonA,NonB hepatitis, the propensity for persistent infections, and the physical properties of the virus were all determined in the chimpanzee prior to the isolation of HCV. The cloning of HCV was dependent on high titer chimpanzee plasma, and the verification of infectious clones could be accomplished only in this animal model. Immunological analyses in HCV infected chimpanzees have been essential in defining the immune correlates of viral clearance and the failed immune response in persistent infections. The chimpanzee is the only animal suitable for vaccine development, and the knowledge gained from chimpanzee studies has brought us closer to that realization. Analysis of hepatic gene expression in the chimpanzee has revealed signature changes in the innate immune response to HCV and the basis for the lack of response to IFN in null responders. Chimpanzees are often the last stage of preclinical development for antivirals and new therapeutics progressing to human trials. Although the chimpanzee is indispensible for many studies, the marmoset model of GBV-B infection and immunodeficient mice with mouse/human chimeric livers are important surrogate models. The identification of HCV receptors and many host factors essential for replication suggest that the future may hold a mouse fully susceptible to HCV infection.
7. Hepatitis C Virus Drug Pipeline Overview and Clinical Trial Design
In the last decade, insights into the virology of hepatitis C virus (HCV) have unraveled several targets for potential novel therapeutics that, unlike interferon (IFN)-alpha and ribavirin, are specifically targeted to HCV. Many such direct-acting antiviral (DAA) drugs are at the preclinical developmental stage and several are in clinical development. Initial clinical trials using some of these inhibitors, either alone or in combination with pegylated IFN-alpha and ribavirin, have yielded encouraging results.
8. Clinical Virology Support for HCV Drug Development
Yupeng He, Liangjun Lu and Akhteruzzaman Molla
Clinical virology studies are integral to the antiviral drug development and approval process by providing critical information and guidance to allow optimal trial designs, timely treatment decisions, and effective therapy monitoring. A main focus and high priority of clinical virology research is to monitor and characterize the development of viral drug resistance in drug-treated patients. Numerous viral titer, subtype, genotypic (sequencing) and phenotypic assays, both certified and investigational, are currently available for HCV clinical virology usage. Genotypic and phenotypic analyses of baseline, on- and post-treatment clinical samples are critical to detection and monitoring of drug resistance. Characterization of drug resistance in vitro helps to guide design of clinical studies and help predict or interpret in vivo drug resistance. In this chapter we discuss standard guidelines for HCV clinical virology, followed by a review of the different assays and methods required for a clinical virology study. In the last part, we discuss in vitro HCV antiviral drug resistance study methods and results, and their implications for clinical studies.
9. NS3 Protease Covalent Inhibitors
Kevin X. Chen and F. George Njoroge
The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It is one of the most attractive targets for developing novel antiviral therapies. Two distinct classes of NS3 protease inhibitors have emerged with different mechanisms of action: non-covalent classical inhibitors and covalent inhibitors. Several types of warheads for covalent bonding have been studied. Among them, the ketoamides have been the most successful class of covalent inhibitors. In fact, the two most clinically advanced HCV NS3 protease drug candidates are both ketoamides: boceprevir and telapravir, in phase III clinical trials. This chapter reviews the evolution and development of covalent NS3 protease inhibitors from early structure-activity-relationship investigations to late stage clinical candidates.
10. NS3 Protease Non-covalent Inhibitors
Brad O. Buckman, Karl Kossen, John B. Nicholas and Scott D. Seiwert
Progress is rapidly being made to improve the standard of care for chronic hepatitis C (HCV), which currently requires long durations of weekly pegylated interferon (peg-IFN) injections in combination with twice daily orally administered ribavirin (RBV). More effective future treatments are likely to include direct acting antiviral agents (DAAs). Several small, orally active non-covalent peptidomimetic inhibitors of NS3/4A protease have demonstrated potent reduction of HCV RNA and promising safety profiles in HCV infected patients. These agents may represent important components of future therapies. Here, the discovery, preclinical and clinical characteristics of these inhibitors are described.
11. Discovery of Hepatitis C Virus NS3-NS4A Complex Inhibitors
Mingjun Huang, Kathe Stauber, Atul Agarwal, Milind Deshpande and Avinash Phadke
Hepatitis C virus (HCV) infection is a serious global health problem because of its high prevalence, chronic nature and significant morbidity of the resulting diseases. The current standard of care (peginterferon α-2a/b and ribavirin combination) is limited by numerous side-effects and suboptimal efficacy in genotype-1 HCV-infected patients underscoring the unmet medical need for new therapies. Here we describe our efforts in discovery and optimization of a novel series of specific inhibitors leading to the nomination of ACH-806 (or GS-9132) for clinical development. These inhibitors interrupt the functions of HCV NS3-NS4A complex likely by binding to NS4A. We have summarized our studies on antiviral activity, resistance induction, mechanism of action, and pharmacokinetics with selected inhibitors including ACH-806. Finally, we present the data on a proof-of concept clinical trial with ACH-806 that validates this novel mechanism of action.
12. Hepatitis C Virus NS3 Helicase Inhibitors
Craig A. Belon and David N. Frick
The hepatitis C virus (HCV) nonstructural protein 3 (NS3) is a complex multifunctional enzyme. In addition to processing the viral polyprotein, NS3 functions as a viral helicase capable of separating duplex RNA and DNA in reactions fueled by ATP hydrolysis. A functioning helicase is necessary for HCV replication, showing that the NS3 helicase could be an antiviral drug target. Although early screens for HCV helicase inhibitors yielded few if any antiviral leads, more recent studies have found potent helicase inhibitors that are active against the HCV replicon. Noteworthy HCV helicase inhibitors that are relatively non-toxic to cells and inhibit the HCV replicon include triphenylmethanes, acridones, amidinoantrhracyclines, and a rationally designed substituted pyrrole. Also discussed here are assay systems available for discovering and analyzing HCV helicase inhibitors, which can broadly be grouped into two categories: those that measure helicase-catalyzed hydrolysis of ATP, and those that measure helicase-catalyzed separation of double-stranded nucleic acid substrates.
13. NS4B Targets and Inhibitors
Menashe Elazar and Jeffrey S. Glenn
Hepatitis C virus (HCV) non-structural protein 4B (NS4B) is emerging as a major target for antiviral intervention. NS4Bs crucial role in different aspects of HCVs life cycle and newly identified functions of this protein enabled development of specific assays that were utilized for high-throughput small molecule screens, which in turn lead to identification of small molecules inhibitors of NS4B functions and HCV replication some of which are undergoing clinical evaluation and preclinical development. In this review we highlight the recent identification of small molecule inhibitors that targets NS4Bs RNA binding activity and an AH-mediated membrane interaction. We further discuss the potential of other candidate activities or domains within NS4B that may serve as targets for antiviral intervention.
14. NS5A Inhibitors
Pilar Najarro, Neil Mathews and Stuart Cockerill
The HCV NS5A protein plays critical roles in the life cycle of the virus and has been associated with a multitude of host-pathogen events associated with NS5A. As part of the replication complex, it is essential for RNA replication. In addition, its propensity to engage in many protein-protein interactions enables this protein to facilitate the assembly of viral particles and to counteract the host immune response. However, the inherent intractability of NS5A as a drug target has caused it to be of low priority in the "rational drug hunter" portfolio of anti-viral arsenals. A lack of enzymatic or receptor functionality, a paucity of structural data and limited evidence for an ability to directly bind small molecules have all conspired against it. The development of HCV subgenomic replicon technology provided an opportunity to identify inhibitors of HCV with mechanisms distinct from the established targets, i.e. polymerase and protease. Whole cell screening using the replicon technology and subsequent generation of replicon mutants has pointed to NS5A as being the likely target of a number of hit compounds A number of companies have now developed, through lead optimisation, highly selective and potent inhibitors of NS5A. Recently these efforts have culminated in a clinical proof of concept and established NS5A as a valid target for development of small-molecule therapies.
15. Nucleoside inhibitors of Hepatitis C Virus
Klaus Klumpp and Mark Smith
Nucleoside analogs have transformed our ability to treat viral diseases and have contributed to a significant reduction in morbidity, mortality and suffering worldwide caused by viral infections, including Human Immunodeficiency Virus (HIV), Hepatitis B Virus and Herpes Virus infections. Similarly, nucleoside analogs hold great promise to also become the backbone of the future standard of care for the treatment of Hepatitis C Virus infection, because the currently available data suggest that nucleoside analogs can provide high antiviral potency, a high barrier to resistance selection, antiviral potency across the whole spectrum of Hepatitis C Virus genotypes and favorable properties for combination with other antiviral agents. This chapter summarizes efforts in antiviral research that have led to the discovery of Valopicitabine (NM283), Balapiravir (R1626) and R7128 (RG7128). Current efforts aim to further improve efficacy by optimizing nucleoside intrinsic potency, phosphorylation efficiency and delivery of antiviral nucleoside analogs.
16. NS5B Polymerase Non-Nucleoside Inhibitors
Martijn Fenaux and Hongmei Mo
The inhibitors of HCV NS5B polymerase consist of 2 classes: nucleoside inhibitors and non-nucleoside inhibitors. In contrast to the nucleoside inhibitors which bind to the active Site of the polymerase, the HCV non-nucleoside polymerase inhibitors binds to one of the four allosteric binding Sites within the NS5B polymerase including: Site 1 (Thumb I) for JTK-109, Site II (Thumb II) for PF-868554, VCH-759, VCH-916 and VCH-222, Site III (Palm I) for ANA-598, A-848837 and ABT-333, and Site IV (Palm II) for HCV-796. Among these non-nucleoside inhibitors, HCV-796 was the first inhibitor to show an antiviral effect in HCV-infected patients. However, the development of this compound was discontinued due to the hepatic toxicity. Subsequently, PF-868554, VCH-759, VCH-916, VCH-222, ANA-598, and ABT-333 demonstrated antiviral activity in early clinical trials and some have been advanced to phase II. Due to their distinctive binding sites, non-nucleoside polymerase inhibitors selected different NS5B mutations which exhibited non-cross-resistance profiles. Therefore, combination of non-nucleoside inhibitors may reduce the development of resistance. Given the importance of the NS5B non-nucleoside polymerase inhibitors for the treatment of HCV, this chapter will describes the preclinical resistance profiles as well as the clinical results of the above inhibitors.
17. Hepatitis C Virus Glycoprotein-dependent Entry
H.E. Drummer and J.A. McKeating
Glycoprotein E1 and E2 are type 1 transmembrane proteins that are cleaved from the polyprotein through the action of signal peptidases in the endoplasmic reticulum (ER) where they form disulfide linked and non disulfide linked heterodimers. The native folding of E1 and E2 is highly dependent on their coexpression, although a subdomain of E2 can be expressed in isolation that retains receptor binding properties (sE2). The HCV glycoproteins are distantly related to the phylogenetically related flavivirus glycoproteins prM and E, although sequence comparisons together with functional and structural studies suggest significant divergence. HCV research was severely restricted by the inability to propagate the virus in cultured cells. The recent development of the JFH-1 HCVcc system has enabled rapid discoveries in all areas of HCV research, including the discovery of viral entry factors. The detailed mechanism(s) of HCV entry into polarized cells awaits further investigation. It will be interesting to see the role of entry inhibitors in future combination therapies for the treatment of chronic HCV infection.
18. A Perspective on Host Cell Targets and Inhibitors
HCV drug discovery efforts have been mainly focusing on two viral targets, NS3 protease and NS5B polymerase, which are essential for viral replication. However, due to the high heterogeneity and high replication and mutation rates of the virus, resistance emerges quickly in patients treated with specific inhibitors of these viral enzymes. A complementary strategy is to target cellular proteins that are required for viral replication, which may have the advantage of higher genetic barrier to resistance and broader genotype coverage. Through siRNA screen and chemogenetic approach, a number of potential host targets have been identified at essentially every step of viral life cycle, including viral entry, genome replication, virion assembly and release. Some are engaged in viral replication through direct interaction with HCV proteins, such as cyclophilins. Others modulate viral life cycle via various cellular pathways, such as lipid metabolism and membrane trafficking. There exist both opportunities and challenges in developing host targeting antivirals. Currently the most advanced compounds are cyclophilin inhibitors in Ph II. The combination of host and viral targeting inhibitors presents a highly attractive strategy to suppress the emergence of resistance and maximize antiviral efficacy.
19. Targeting Innate Immunity for HCV Antiviral Therapy
Michael Gale and Jr.
The ability of HCV to mediate persistent, life-long infection in its human host is linked to a poor response rate to the current interferon-based therapy for treatment of infection. Future antiviral therapy against HCV protein products will most certainly be met with challenges due to virus resistance. Molecular studies of HCV-host interactions have revealed how innate immune programs of the host can suppress HCV infection and support immune amplification. Therapeutic strategies to target these host features and factors may provide potent new approaches to HCV treatment through immune enhancement while minimizing the likelihood that HCV will resist such actions.
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(EAN: 9781904455783 9781912530618 Subjects: [virology] [microbiology] [medical microbiology] [molecular microbiology] )