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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 11, 2006
Contents
Recent Advances in Antiviral Agents
Executive Editor: Shin-Ru Shih
Editorial Pp. 1299
Antiviral Drug Discovery Targeting to Viral Proteases
Pp. 1301-1314
J.T.A. Hsu, H-C. Wang, G-W Chen and S- Shih
[Abstract]
Understanding Helicases as a Means of Virus Control
Pp. 1315-1338
D.N. Frick and A. M.I. Lam
[Abstract]
Antiviral Therapy Targeting Viral Polymerase Pp.
1339-1355
C-H. Tsai, P. Y. Lee, V. Stollar and M-L. Li
[Abstract]
Herpes Simplex Viruses in Antiviral Drug Discovery Pp.
1357-1370
L.M. Schang
[Abstract]
Recent Advances in Antiviral Agents: Antiviral Drug
Discovery for Hepatitis Viruses Pp. 1371-1377
K. Tanikawa
[Abstract]
Current Status of Anti-Picornavirus Therapies Pp.
1379-1390
D.L. Barnard
[Abstract]
New Strategies for Immune-Mediated Anti-Viral Drug
and Vaccine Development Pp. 1391-1401
C-C. Chen and Y. Ron
[Abstract]
General Articles
Soft Condensed Matter in Pharmaceutical Design Pp.
1403-1419
G. Paradossi, F. Cavalieri and E. Chiessi
[Abstract]
Porcine Cytochrome P450 and Metabolism Pp.
1421-1427
M.T. Skaanild
[Abstract]
Abstracts
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to top]
Editorial
Recent Advances in Antiviral Agents
Over 400 pathogenic viruses that infect humans
have been identified. Moreover, newly emerging viruses, such
as SARS-CoV, and avian flu, post a constant threat. Unfortunately,
only limited approved treatments exist for viral infections.
Therefore, it is urgent and crucial to develop more effective
and nontoxic antiviral agents.
In preparation this issue, we have sought to provide useful
information for scientists with an interest in antiviral research.
These studies review the current status of drug discovery
based on specific molecular targets in virus infection, or
focus on specific virus families.
In the first article, Hsu and Coworkers [1] focused on viral
protease as the molecular targets for the development of antiviral
agents. Viral protease usually plays an essential role in
viral replication. Viral polypeptide must be further cleaved
by viral protease to create mature, functional protein. The
fact that several FDA-approved protease inhibitors can effectively
treat HIV-1 patients and a class of hepatitis C virus protease
inhibitors can reduce HCV RNA levels in patient’s plasma
highlighted the considerable potential of viral protease as
the molecular target for antiviral drug discovery. This paper
not only summarizes the classification, biochemical property,
and functional role of viral protease, but also reviews the
specific protease inhibitors for each virus. Notably, some
protease inhibitors can inhibit more than one virus, for example,
an anti-HIV agent also acts as a SARS-CoV 3CLpro inhibitor.
Consequently, understanding the molecular features of each
viral protease can help in developing effective antiviral
therapies.
Frick and Lam [2] discussed recent progress in antiviral research
based on viral helicase as the molecular target. Helicases
are essential for viral genome replication, transcription
and translation. Numerous potent helicase inhibitors have
been demonstrated to reduce viral replication in cell cultures
and animal models, such as SF1 helicase inhibitors against
HSV and SARS-CoV; SF2 helicase inhibitors against HCV, West
Nile virus and JEV; and SF3 helicase inhibitors against HPV.
This article also discusses in detail the classification,
structure and function of viral helicases. All viral helicases
share a common motor function fueled by ATP hydrolysis, but
differ in precisely how the motor moves the protein and its
cargo on a nucleic acid chain. The mechanism of these helicases
inhibitors is based on influencing rates of helicase-catalyzed
viral DNA or RNA unwinding by preventing ATP hydrolysis, nucleic
acid binding, nucleic acid release, or disrupting the interaction
of a helicase with a required cofactor.
Tsai and coworkers [3] focused on the current antiviral research
based on viral polymerase as the molecular target. Polymerase
has been classified into four classes, RNA-dependent RNA polymerase
(RDRPs), DNA-dependent RNA polymerase (DDRPs), RNA-dependent
DNA polymerase (reverse transcriptase) and DNA-dependent DNA
polymerase (DNA pol). All of these polymerases share common
structures and functions, but have different specific features
for different viral polymerases. For example, cap-snatching
activity is a specific and unique feature for influenza viral
RDRP. This article discusses in details not only about the
inhibition modes of antiviral compounds targeting to viral
polymerase, but also addresses the resistance mechanism of
these antiviral agents. The success of anti-HSV therapy by
acyclovir and anti-HIV therapy by AZT strongly indicated that
intensive structural and functional studies of viral polymerases
are potentially important in developing more effective antiviral
therapy.
Schang [4] reviewed antiviral drug discovery for herpes simplex
viruses (HSV). The first efficacious and safe antivirals were
developed against HSV. However, the emergence of drug-resistant
viral strains creates some limitations in viral polymerase
inhibitors. Schang pointed out that cellular proteins are
currently considered to be alternative potential targets for
novel anti-HSV agents. Schang described the discovery of pharmacological
CDK inhibitors (PCIs). CDKs are a family of cellular protein
kinases that are employed for HSV replication. CDK2 has been
shown to be nonessential for mammals, and has overcome concerns
regarding the restriction of PCIs. Furthermore, PCIs hinder
the selection of drug-resistant mutants, and are effective
against strains that have developed resistance to conventional
antiviral drugs. PCIs are also active against various unrelated
viruses, which makes them promising as drugs against new emerging
viral diseases.
Tanikawa [5] discussed the current development of antivirals
against hepatitis viruses, with an emphasis on HBV and HCV.
Estimates indicate that 350 million people are infected with
HBV and 170 million people with HCV. Chronic HBV and HCV infections
are significant causes of end-stage liver disease and hepatocellular
carcinoma (HCC). This article discusses currently clinical
used anti-HBV and anti-HCV agents in detail, for example,
interferon (IFN), lamivudine and adefovir for HBV; and Pegylated
IFN (Peg IFN) plus ribavirin combination therapy for HCV.
Tanikawa also reviewed the antiviral efficacy in clinical
trails for other nucleoside analogues, such as emtricitabine,
telbivudine, and clevudine.
Barnard [6] discussed the current status of anti-picornavirus
therapy. Picornaviruses are important human pathogens that
cause significant morbidity and mortality. Although no approved
treatments exist, some antiviral agents against rhinoviruses
and enteroviruses have displayed promising results in clinical
trails. These potential anti-picornaviral compounds have diverse
molecular targets. Anti-picornavirus agents include capsid
binder inhibitors, viral RNA synthesis inhibitors, 3C protease
inhibitors, siRNA, and natural compounds with unknown mechanisms.
Barnard provided updated information regarding animal studies
and clinical trails of these inhibitors. This paper also pointed
out that no therapies exist and few drugs have been discovered
for certain enteroviruses, such as echoviruses, indicating
a strong need for potent and nontoxic compounds against enterovirus
infections.
Finally, Chen and Ron [7] stresses new strategies for immune-mediated
anti-viral drug and vaccine development. Although the drugs
targeting specific viral molecules exhibit excellent treatment
potential, the involvement of the immune system is crucial
for complete recovery and preventing reinfection. Both the
humoral and cellular arms of the immune response play an important
role in combating viral infections. For example, cytokines,
as potent stimulators of immune response, have been thoroughly
studied and employed in humans and experimental animals as
antivirals. Moreover, the successful production of human antiviral
monoclonal antibodies provides a promising and efficacious
method of antiviral therapy. Chen and Ron also reviewed current
development of antiviral vaccines , with an emphasize on recombinant
attenuated vaccines. Several chimeric viral vaccines have
proven efficacious in animals and are now in different phases
of clinical trails.
In conclusion, the outstanding articles presented in this
issue provide current advances of development of antiviral
agents. These articles can help to bring virologists, chemists,
basic medical researchers, and clinical physicians up to date
on antiviral researches.
References
[1] Hsu JA, Wang HC, Chen GW, Shih SR. Antiviral drug discovery
targeting to viral proteases. Curr Pharm Design 2006; 12(11):
1301-1314.
[2] Frick DN, Lam AMI. Understanding helicases as a means
of virus control. Curr Pharm Design 2006; 12(11): 1315-1338.
[3] Tsai CH, Lee PY, Stollar V, Li ML. Antiviral therapy targeting
viral polymerase.Curr Pharm Design 2006; 12(11): 1339-1355.
[4] Schang LM. Herpes simplex viruses in antiviral drug discovery.
Curr Pharm Design 2006; 12(11): 1357-1370.
[5] Tanikawa K. Antiviral drug discovery for hepatitis viruses.
Curr Pharm Design 2006; 12(11): 1371-1377.
[6] Barnard DL. Current status of anti-picornavirus therapies.
Curr Pharm Design 2006; 12(11): 1379-1390.
[7] Chen C. Ron Y. New strategies for immune-mediated anti-viral
drug and vaccine development. Curr Pharm Design 2006; 12(11):
1391-1401.
Shin-Ru Shih, Ph.D.
Professor/Chair
Graduate Institute of Medical Biotechnology
& Department of Medical Biotechnology
and Laboratory Science
Chang Gung University
259 Wen-Hua 1st Road
Kwei-Shan, Taoyuan
Taiwan
E-mail: srshih@mail.cgu.edu.tw
[Back to top]
Antiviral Drug Discovery Targeting to Viral Proteases
J.T.A. Hsu, H-C. Wang, G-W Chen and S- Shih
Proteases fulfill multiple roles in health and disease, and
considerable interest has been expressed in the design and
development of synthetic inhibitors of disease-related proteases.
Virus-encoded proteases have been shown to be involved in
the replication of many viruses. The success of anti-HIV-1
therapy using specific and potent protease inhibitors suggests
that viral proteases can be the valid molecular targets for
the development of antiviral drugs against other viruses.
Intensive genetic and biochemical studies have been conducted
on viral proteases and new insights and results are rapidly
emerging. This work reviews features of viral proteases with
respective to the development of effective antiviral therapy.
[Back to top]
Understanding Helicases as a Means of Virus Control
D.N. Frick and A. M.I. Lam
Helicases are promising antiviral drug targets because their
enzymatic activities are essential for viral genome replication,
transcription, and translation. Numerous potent inhibitors
of helicases encoded by herpes simplex virus, severe acute
respiratory syndrome coronavirus, hepatitis C virus, Japanese
encephalitis virus, West Nile virus, and human papillomavirus
have been recently reported in the scientific literature.
Some inhibitors have also been shown to decrease viral replication
in cell culture and animal models. This review discusses recent
progress in understanding the structure and function of viral
helicases to help clarify how these potential antiviral compounds
function and to facilitate the design of better inhibitors.
The above helicases and all related viral proteins are classified
here based on their evolutionary and functional similarities,
and the key mechanistic features of each group are noted.
All helicases share a common motor function fueled by ATP
hydrolysis, but differ in exactly how the motor moves the
protein and its cargo on a nucleic acid chain. The helicase
inhibitors discussed here influence rates of helicase-catalyzed
DNA (or RNA) unwinding by preventing ATP hydrolysis, nucleic
acid binding, nucleic acid release, or by disrupting the interaction
of a helicase with a required cofactor.
[Back to top]
Antiviral Therapy Targeting Viral Polymerase
C-H. Tsai, P. Y. Lee, V. Stollar and M-L. Li
Viral DNA and RNA polymerases are enzymes, which are responsible
for copying the genetic materials of viruses and are therefore
central components in the life cycles of viruses. The polymerases
are essentially required for the replication of viruses. The
reverse transcriptase (RT) of the retroviruses and the hepadnaviruses
is the sole viral enzyme required for the synthesis of DNA
from viral RNA. Viral polymerases are therefore an extremely
favorable target for the development of antiviral therapy.
The success of anti-HIV-1 therapy using inhibitors specifically
targeting HIV RT suggests that other viral polymerases can
be the valid molecular targets for the design of antiviral
drugs. Intensive structural and functional studies of viral
polymerases have been conducted and have opened new avenues
for the development of more effective antiviral therapy. This
review summarizes the insights gained from recent structural
and functional studies of antiviral agents, which target viral
polymearses. The primary focus will be on hepatitis C virus
(HCV), herpesviruses, HIV, hepatitis B virus (HBV) and influenza
virus.
[Back to top]
Herpes Simplex Viruses in Antiviral Drug Discovery
L.M. Schang
Since the 1950’s, herpes simplex viruses (HSV) have
played prominent roles in the development of antivirals. The
first efficacious antivirals, as well as the first safe for
systemic use, were developed against HSV. It was only in 1995
when the first antiviral against a target not validated first
with HSV was approved for clinical use (sequinavir). The early
successes of targeting HSV DNA replication were most influential
in developing the concept that antiviral drugs must target
viral proteins. Such concept has ensured the safety of current
antiviral drugs, which all target viral proteins. Current
antivirals have proven to have no major negative effects on
non-infected cells or treated patients. Because of their success
widespread and use, however, these drugs have been found to
have some limitations. Perhaps the clinically most important
one is their ability to promptly select for drug-resistant
viral strains. Owing to such limitations, cellular proteins
are now considered as valid targets for novel antiviral drugs.
The discovery that pharmacological CDK inhibitors (PCIs) inhibit
HSV replication through novel mechanisms played a major role
in this new appreciation of cellular proteins as potential
targets for antivirals. This appreciation is reflected in
the scheduling of PCIs to enter clinical trials as antivirals
(against HIV). Herein, we will review the roles of HSV as
model viruses in the discovery and development of antiviral
drugs. The major focus will be on the recent discovery on
the activities of PCIs against HSV and other viruses.
[Back to top]
Recent Advances in Antiviral Agents: Antiviral Drug
Discovery for Hepatitis Viruses
K. Tanikawa
Hepatitis B virus (HBV)- or hepatitis C virus (HCV)- associated
liver diseases are now one of the important health problems
in the world because of the high numbers of patients and the
serious consequences. Recently, however, relatively effective
treatments with antiviral agents have become available. Interferon
(IFN), lamivudine and adefovir are now approved for treatment
of HBV-associated liver diseases and they have been shown
to be fairly effective. The goal of treatments for HBV-associated
liver disease is to achieve a clinical cure in as short a
period as possible without producing resistance mutation of
the virus. Several nucleotide analogues with more potent antiviral
activities are now in clinical trials.
In the case of HCV-associated liver diseases, Pegylated IFN
(Peg IFN) + ribavirin combination therapy is the standard
and most effective treatment with a sustained response of
60-70%. The goal of the treatments for these liver diseases
is to induce the complete eradication of the infected virus
and at present new anti HCV drugs targeting the molecular
segments of the virus are under development. It is expected
that the complete eradication of infected virus will be possible
in most cases in the near future.
[Back to top]
Current Status of Anti-Picornavirus Therapies
D.L. Barnard
Picornaviruses are important human pathogens causing severe
morbidity and some mortality with the potential to cause worldwide
crippling disease. Currently, there are few treatments for
many of the viruses in the Picornaviridae, For rhinoviruses,
there are no approved treatments, although ruprintrivir looks
promising in clinical trials and pyridazinyl oxime ethers
may prove useful. Poliovirus treatments are needed to supplement
the World Health Organization’s polio eradication plan
in order to treat infections caused by reversion of the attenuated
vaccine virus and to supplement vaccine coverage control in
polio endemic areas. However, no promising compounds for treatment
of poliovirus have been developed due to the efficacy of the
vaccines in use. Broad-spectrum inhibitors developed for other
picornavirus may be useful for poliovirus infections. Coxsackievirus
infections in children and in infants are being treated with
pleconaril with some efficacy in reducing mortality and improving
recovery, albeit the treatment is often on a compassionate
use basis. There are no therapies for echovirus infections.
Very little drug discovery research is being done to develop
inhibitors for echo-virus infections, probably due to the
broad-spectrum inhibition exhibited by capsid binding agents
and protease inhibitors discovered for treatment of other
picornaviruses. For example, pyridazinyl oxime ethers are
inhibitory to most echo-viruses. Treatments for enterovirus
infections are also limited, although in a small clinical
trial, milrinone seemed to reduce mortality and improve recovery
from EV71-induced pulmonary edema. Thus, these results strongly
emphasize the need for the development of potent and nontoxic
compounds for the treatment of picornavirus infections.
[Back to top]
New Strategies for Immune-Mediated Anti-Viral Drug
and Vaccine Development
C-C. Chen and Y. Ron
Substantial progress in the development of new anti-viral
drugs has taken place in recent years. Most of these new drugs
belong to three groups of compounds, nucleoside analogs, thymidine
kinase-dependent nucleotide analogs and specific viral enzyme
inhibitors. Although these drugs revolutionized the treatment
of several viral diseases, the involvement of the immune system
is crucial for complete recovery and prevention of reinfection.
New advances in the understanding of immune regulation mechanisms,
mainly the role of cytokines, led to the development of several
new immunologically-based anti-viral drugs and treatments.
The most studied group of immunomodulators is the cytokines,
some of which were shown to act as potent stimulators of immune
responses. Other, non-cytokine immune modulators have also
been successfully employed in both humans and experimental
animals as anti-viral drugs of which several are currently
in clinical trials. Advances in genetic engineering and transgenic
mouse technologies facilitated the production of humanized
as well as authentic human anti-viral monoclonal antibodies.
Some of these antibodies proved to be clinically efficacious
and are commercially produced as anti-viral drugs. As is often
the case in anti-viral treatments, a combination of conventional
and an immune-mediated anti-viral drugs or a combination therapy
involving immunomodulators, therapeutic vaccines, immune intervention
and even gene therapy might prove most efficacious as a treatment
for a particular virus.
Most of the advances made in anti-viral treatments have also
been applied to the development of new vaccines. Some of the
classical attenuated viruses are being replaced by recombinant
attenuated viruses. Recombinant viral vaccines containing
genes encoding other viral antigens and/or cytokines are being
tested as new vaccines. Several chimeric viral vaccines have
proven efficacious in experimental animals and are now in
different phases of clinical trials. This review will encompass
the major new developments in this field, including some that
have not yet been subjected to human trials.
[Back to top]
Soft Condensed Matter in Pharmaceutical Design
G. Paradossi, F. Cavalieri and E. Chiessi
In recent years pharmaceutical design
has been facing the needs expressed by new therapeutic methodologies
such as gene therapy, targeted delivery and closely related
diagnostic fields as contrast enhancing agents for ultrasonic
investigations. In this context pharmaceutical research has
diversified the efforts toward a more integrated approach
where the efficacy of an active molecule is enhanced and assisted
by the surrounding carrier. Usually this drug platform is
a hydrogel matrix, a multicomponent system constituted by
an aqueous solution and a polymeric moiety imparting different
functions to the matrix, as responsiveness to external stimuli,
affinity to receptors, controlled drug release. Such devices
represent one of the leading topics of the soft condensed
matter recent research, a domain where physics, chemistry
and bioengineering cross each other with the aim to achieve
an integrated description of these materials. In this respect
modern drug design will make use more and more of concepts
proper of soft condensed polymer and colloidal sciences.
In this review we will describe the state-of-art in the field
of the matrices used in innovative drug formulations with
a particular emphasis on the implications to pharmaceutical
design along with the experimental and theoretical investigation
tools worked out in the last decade.
[Back to top]
Porcine Cytochrome P450 and Metabolism
M.T. Skaanild
The pig and especially the minipig are becoming
increasingly used as a test animal both in pharmacological
and toxicological testing of new compounds. The minipig is
used because of its size, it is easy to handle and less test
substrate is required. When using an animal species for testing
it is of importance to know if the test animal’s posses
the same abilities to metabolize drugs as humans. Some of
the P450 enzymes have been characterized in the pig regarding
substrate specificity, inhibition and regulation. The porcine
enzymes CYP1A, CYP2A and CYP3A all metabolize the same test
substrates as the human enzymes, whereas the enzymes CYP2B,
CYP2D, and CYP2E in pig on the other hand seem to be different
from the human enzymes concerning metabolism of the well know
test substrates. Some of the porcine enzymes have been sequenced
i.e. CYP1A, CYP2A, CYP2B, CYP2D, CYP2E and CYP3A and not surprisingly
the porcine CYPs that metabolize the human test substrates
are about 75% identical in cDNA sequences.
What is needed is inhibitory antibodies against each of the
porcine enzymes, in order to test whether a test compound
is metabolized by one or the other enzyme. Until now chemical
inhibitors have been used, but they are rarely 100% specific.
Anti-human inhibitory antibodies have also been used, but
they may not recognize the porcine enzyme and therefore will
not inhibit the reaction. Antibodies for immunoblotting would
also make it possible to estimate how much of the total P450
the individual enzymes comprise. From what is known about
the porcine P450, it can be concluded that the pig seems to
be a good test species if CYP1A, CYP2A or CYP3A are involved
in the metabolism of the test compound, depending on the contribution
of other enzymes in competing pathways.
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