Current Drug Targets - Infectious Disorders, Volume 3, No. 3, 2003
Contents
Targeting NS5B RNA-Dependent RNA Polymerase
for Anti-HCV Chemotherapy
Pp. 207-219
Jim Zhen Wu and Zhi Hong
Molecular Targets for Papillomavirus Therapy Pp. 221-239
V. G. Wilson and G. Rosas-Acosta
Exploiting New Potential Targets for Anti-Hepatitis
B Virus Drugs Pp. 241-246
Y-M Wen , X Lin and
Z-M Ma
Current and Future Therapy for Chronic
Hepatitis C Virus Liver Disease
Pp. 247-253
G. Lake-Bakaar
Vaccine Development for Potential
Bioterrorism Agents Pp.
255-262
R.W. Titball , and
E.D. Williamson
Vaccinia Vectors as Candidate Vaccines: The
Development of Modified Vaccinia Virus Ankara for Antigen Delivery Pp. 263-271
Gerd Sutter and Caroline Staib
[Back to top] Targeting NS5B RNA-Dependent RNA Polymerase
for Anti-HCV Chemotherapy
Jim Zhen Wu
and Zhi Hong
The global prevalence of persistent hepatitis C virus (HCV) infection and the lack of a highly effective and well-tolerated antiviral therapy have spurred intensive efforts to discover and develop novel anti-HCV therapy in the pharmaceutical industry. HCV NS5B RNA-dependent RNA polymerase (RdRp), the centerpiece for viral replication, constitutes a valid target for drug discovery. Compared to the host RNA and DNA polymerases, NS5B RdRp has distinct subcellular localization at the interface of the endoplasmic reticulum (ER) membrane and cytoplasm, a novel catalytic mechanism and many unique structural features, all of which make it an attractive target for developing effective anti-HCV therapeutics. High genetic variation among the major HCV genotypes commands that any efficacious NS5B inhibitors have to be broadly active against NS5Bs from various genotypes. Rapid viral replication and its inherent genetic diversity will certainly culminate drug resistance to any NS5B inhibitors. Therefore, iterative drug design and combination therapies of drugs that intervene with different steps in the HCV replicative cycle are needed to combat the viral infection. Many classes of nucleoside and non-nucleoside inhibitors of NS5B RdRp have been identified and appeared in literatures and patent applications. These progresses hold a considerable promise to the development of novel, specific and highly effective therapeutics to achieve sustained response and ultimately the eradication of HCV infection.
[Back to top] Molecular Targets for Papillomavirus Therapy
V. G. Wilson and G. Rosas-Acosta
Papillomaviruses are infectious agents for human and animal epithelial tissue, and nearly 100 distinct human types (HPVs) have been identified. When these viruses infect cutaneous or mucosal skin they can initially cause clinical warts or persistent infection with little or no visible manifestations. Warts, while usually benign, can be painful or cosmetically unacceptable and often require medical treatment. Furthermore, infection with certain specific HPV types, such as 16 or 18 (as well as several others), is the major risk factor for a woman’s development of cervical cancer. In addition to cervical cancer, papillomaviruses have also been implicated in cancers of the skin and respiratory track though the evidence is not yet as conclusive. It is clear that prevention or elimination of papillomavirus infections would ultimately reduce the incidence of cervical cancer and possibly other epithelial cancers as well. Unfortunately, progress in vaccine development has been slow and no specific anti-papillomavirus agents are available. The rational development of effective anti-papillomaviral treatments will require a detailed understanding of how these viruses replicate and interact with the host cell, and much progress has been made in this area over the last 10 years. These viruses have small DNA genomes with limited coding capacity, and their complete array of viral protein products is known. This review will discuss the known functions of the viral proteins with a focus on strategies to interdict their biological activities as a possible means of specific therapy.
[Back to top] Exploiting New Potential Targets for
Anti-Hepatitis B Virus Drugs
Y-M Wen , X Lin and Z-M Ma
Based on the recent studies of HBV strains with different replication efficiency, several new potential targets for anti-HBV replication have been presented. These include the viral and cellular regulatory factors associated with HBV replication and the process for encapsidation of viral genome and budding into endoplasmic reticulum (ER). A putative regulatory domain has been reported at the carboxyl-end of reverse transcriptase (RT) and when serine is substituted for proline at residue 652 of RT, replication efficiency of HBV is decreased. Substitution of proline for threonine at the 2798 nucleotide of the terminal protein (TP) gene, renders the mutant completely replication deficient. Expression of TP blocks the interferon (IFN) pathway and inhibits the responsive state of cells to interferons ( IFN) a and g . Interference of HBV capsid assembly drastically affects the encapsidation of viral genome, a crucial process for reverse transcription and viral DNA synthesis. Small molecules (bis-ANS) have been reported to act as a “wedge” to misdirect the polymerization of capsid, resulting in inhibition of virus replication. Another new group of compounds (HAP) has been shown to inhibit virus replication and also inhibit the assembly of viral capsid (core particle). Finally the capsids containing HBV genome are enveloped by budding into endoplasmic reticulum and release from virus infected cells, and this morphogenesis and secretion of HBV is dependent on glucosidases in the ER of host cells. Competitive inhibition of these glucosidases has been suggested as strategy against HBV replication.
[Back to top] Current and Future Therapy for Chronic
Hepatitis C Virus Liver Disease
G. Lake-Bakaar
Therapy with recombinant human interferon alpha remains pivotal to the treatment for chronic hepatitis C virus liver disease. Semi-synthetic protein-polymer conjugates of interferon with polyethylene glycol have also been recently developed. These conjugates protect the protein from degradation; reduce the immunogenicity; and prolong exposure to drug by a sustained absorption, restricted volume of distribution and sustained high serum concentration. Therapy with pegylated interferons is associated with significantly greater sustained virological response rates (SVR) compared to the non-pegylated formulation. Ribavirin is a guanosine analog with minimal antiviral activity against HCV. It demonstrates significant clinical synergism when administered in combination with interferon. Amantadine blocks entry of influenza A virus into cells. Used in combination with ribavirin and interferon as triple therapy, it may have some benefit compared to dual or monotherapy. Current treatment with pegylated interferons combined with weight-based ribavirin, provides the highest sustained virological response rates. In the absence of suitable animal models, HCV dynamic studies in man have been helpful in defining the mechanisms of action of interferon in chronic HCV liver disease. Novel therapeutic agents are being developed as the replication cycle of HCV is being understood. However, their safety and efficacy remain to be established and availability for clinical use is unlikely within the next 3 to 5 years. This review describes current antiviral therapy in chronic HCV liver disease, addresses the potential role of viral dynamics in elucidating the mechanisms of action of the drugs and discusses future potential therapeutics agents.
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top]
Vaccine Development for Potential Bioterrorism Agents
R.W. Titball , and E.D. Williamson
Vaccines are considered to be one of the most effective ways of combating disease caused by bioterrorism agents. Such vaccines must be able to provide protection against pathogens which might enter the body by a number of routes, including the respiratory tract. They should also be able to induce protective immunity rapidly and would ideally be given non-invasively. There are few vaccines which currently meet these requirements. In part, this reflects the low level of research on many bioterrorism agents over the past few decades. Little is known about basic mechanisms of pathogenicity of many of these agents. However, by their very nature these agents cause serious disease, and must be handled in high containment laboratories. This requirement also limits the speed and ease with which research on these pathogens can now take place. Against this background, research on vaccines against potential bioterrorism agents is likely to proceed along two lines. Firstly because the genome sequences of most of the principal bioterrorism agents have either been completed or are close to completion, there is likely to be reliance on the exploitation of this information to devise improved vaccines. A number of groups are working on methodologies to identify vaccine antigens directly from genome sequences. Secondly, there will be a need to formulate such vaccines appropriately for the rapid induction of protective immunity after non-invasive delivery. The prospects for the development of a new generation of bioterrorism vaccines which exploit these technologies are reviewed in this manuscript.
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to top]
Vaccinia Vectors as Candidate Vaccines: The Development of Modified Vaccinia
Virus Ankara for Antigen Delivery
Gerd Sutter
and Caroline Staib
Vaccinia viruses engineered to express foreign genes are powerful vectors for production of recombinant proteins. Originating from highly efficacious vaccines securing world-wide eradication of smallpox, the most appealing use of vaccinia vectors is to serve as vaccine delivery system for heterologous antigens. Concerns about the safety of vaccinia virus have been addressed by the development of vectors based on attenuated viruses. One of them, modified vaccinia virus Ankara (MVA) can be considered as current vaccinia virus strain of choice for clinical investigation. Historical development and use of MVA as vaccine against smallpox allowed to establish an extraordinary safety profile. MVA can be used under conditions of biosafety level 1 because of its avirulence and its deficiency to productively grow in human cells. In recent years significant progress has been made with regard to the development of MVA vector technologies. Compared to replication competent vaccinia viruses, MVA provides similar levels of recombinant gene expression even in nonpermissive cells. In animal models, MVA vaccines have been found immunogenic and protective against various infectious agents including immunodeficiency viruses, influenza, parainfluenza, measles virus, flaviviruses, or plasmodium parasites. By now first data from clinical trials are becoming available. In this article we briefly review history of MVA and state-of-the art technologies with regard to generation of recombinant MVA vaccines, and describe the progress to develop MVA vector vaccines against important infectious diseases.