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Anti-Infective
Agents in Medicinal Chemistry
ISSN: 1871-5214
Anti-Infective Agents in Medicinal
Chemistry
Volume 5, Number 4, October 2006
Contents
Tuberculosis: Current Treatment and New Drug Development
Pp. 331-344
J. Liu and H.P. Ren
[Abstract]
Pharmacological Cyclin-Dependent Kinase Inhibitors
(PCIs) as Potential Antiviral Drugs Pp. 345-355
L.M. Schang
[Abstract]
Quinones and Malaria Pp. 357-366
Jean Fotie
[Abstract]
Antisense DNA and RNA: Potential Therapeutics
for Viral Infection Pp. 367-377
Ji Yuan, Travis Lim, Zhen Liu, Dexin Qiu, Brian Wong,
Honglin Luo, Xiaoning Si, Bruce McManus and Decheng Yang
[Abstract]
Recent Advances in Pegylated Interferon Antiviral
Therapy of Chronic Hepatitis C Pp. 379-387
Carla S. Coffin and Samuel S. Lee
[Abstract]
Nematodes as Models for the Study of the Regulation
of Activity of P-glycoproteins in Multidrug Resistance (MDR)
Pp. 389-402
D. Kerboeuf and M. Riou
[Abstract]
Antifungal Drugs for Systemic Mycosis: An Overview
of Mechanism of Action and Resistance Pp. 403-412
J.S. Hamdan and R.C. Hahn
[Abstract]
Abstracts
[Back to top]
Tuberculosis: Current Treatment and New Drug Development
J. Liu and H.P. Ren
Mycobacterial infections, including tuberculosis (TB)
and leprosy, are infectious diseases of global importance.
Control of TB is complicated by difficulties in administrating
the long-course chemotherapy regimens, the inability to eliminate
latent organisms, and the increasing appearance of multidrug
resistant strains of Mycobacterium tuberculosis.
New drugs for the control of TB are urgently needed, including
developments of short-term antibiotic regimens to minimize
the emergence of drug resistance and new drugs to treat MDR-TB
patients and to eradicate the latent bacteria. Recent years
have witnessed emergence of many new structural classes of
antimycobacterial agents, some of which exhibit promising
activities against susceptible and resistant strains of M.
tuberculosis. In particular, the newly discovered diarylquinoline
with superior antituberculous activity and encouraging results
from recent studies of nitroimidazopyrans and oxazolidinones
have generated considerable excitement. Genetic and biochemical
studies, facilitated by the availability of mycobacterial
genomes, have provided much insight into the biosynthesis
of mycobacterial cell wall and metabolic processes unique
to the pathogen, which reveal many potential drug targets.
Some progresses toward targeting novel enzymes or biochemical
processes have been made. This review summarizes these developments.
Efforts to make use of existing drugs for treatment of TB,
but which are currently marketed for controlling of other
infections, are discussed. In addition, mechanisms of antibiotic
resistance including the mycobacterial cell wall permeability
barrier and novel resistance mechanisms are also discussed.
[Back to top]
Pharmacological Cyclin-Dependent Kinase Inhibitors
(PCIs) as Potential Antiviral Drugs
L.M. Schang
Targeting viral proteins has led to many successful antivirals.
However, such drugs have certain limitations. They rapidly
select for resistance and tend to be active against only a
few related viruses. And a significant time is required to
identify and characterize targets encoded by new viral pathogens,
a major concern in emerging diseases. As a result of such
limitations, cellular proteins are now considered as potential
targets for antivirals. Drugs targeting cellular proteins
required for several viral functions are less likely to promptly
select for drug-resistance and more likely to be active against
a variety of unrelated viruses, which commonly required the
same cellular proteins. They could also be promptly tested
against any emerging viral pathogen, as even distantly related
viruses commonly require the same cellular proteins. Cellular
cyclin-dependent kinases (CDKs) are required for the replication
of many viruses, and specific pharmacological CDK inhibitors
(PCIs) are proving to have only limited side effects in clinical
trials against cancer. In the last years, PCIs have been found
to inhibit replication of several wild-type and drug-resistant
viruses. Two PCIs, roscovitine and flavopiridol, were recently
proven active in a mouse model of HIV-induced disease. Significant
progress has been made toward understanding the antiviral
mechanisms of PCIs. Roscovitine was found to act by a unique
mechanism, which requires no specific viral proteins but is
specific for viral genomes. Consequently, mutations in viral
genes cannot easily overcome inhibition by PCIs; no PCI-resistant
viral mutant has yet been identified. Owing to the strong
antiviral potential shown in cultured cells, their apparently
relative safety in animal models and clinical trials (against
cancer), and their unique antiviral mechanisms, PCIs are tentatively
scheduled to enter clinical trials as antivirals in the near
future.
[Back to top]
Quinones and Malaria
Jean Fotie
The intensive usage and the efficacy of quinoline and
artemisinin antimalarials have led scientists to focus mainly
on these two families of compounds resulting in the other
classes of antimalarial drugs being ignored. Recently atovaquone,
a hydroxy-naphtoquinone derivative, was reported as an effective
antimalarial drug against the multidrug-resistant parasite
with a novel drug mechanism. This discovery, which emerged
from earlier studies, opened a new approach for the design
of new quinone antimalarials. Other well known anthraquinone
antibiotics such as tetracycline and doxycycline have been
in use in malaria prophylaxis for more than three decades.
This review aims to explore the background to the discovery
of existing quinone antimalarials, and the advance in the
chemistry and biochemistry of synthetic and naturally occurring
quinones with antimalarial activity. Reactions and metabolism
of antimalarial quinones in animals and men are considered,
focusing on compounds that are or have been used to treat
human malaria, with an emphasis on the relationship between
metabolism and biological effects.
[Back to top]
Antisense DNA and RNA: Potential Therapeutics
for Viral Infection
Ji Yuan, Travis Lim, Zhen Liu, Dexin Qiu, Brian Wong,
Honglin Luo, Xiaoning Si, Bruce McManus and Decheng Yang
Antisense DNA and RNA are valuable tools to inhibit expression
of a target gene in a sequence-specific manner. These molecules
are not only widely used for gene functional study but also
for therapeutic purpose. The strategy for therapeutics is
attributed to its specific inhibition of gene expression of
pathogens or disease-causing genes. Three types of anti-mRNA
strategies can be distinguished, including antisense oligodeoxynucleotide
(AODN), nucleic acid enzymes, and double-stranded small interfering
RNA (siRNA). In this article we overview the basic principles
of AODN and siRNA and then focus on their potential applications
in antiviral therapy including our own data on coxsackieviral
infection, a common pathogen of human myocarditis. In addition,
we also briefly discuss the problems and difficulties in these
drug developments, which need to be overcome to achieve the
final goal in clinical application.
[Back to top]
Recent Advances in Pegylated Interferon Antiviral
Therapy of Chronic Hepatitis C
Carla S. Co ffin and Samuel S. Lee
Effective hepatitis C antiviral treatment is
important given the significant global morbidity and mortality
from liver-related complications. Therapy for hepatitis C
has advanced remarkably in the past two decades starting with
interferon-alpha (IFN) monotherapy, followed by genetically
engineered recombinant interferons (consensus IFN alpha) and
subsequently IFN alpha in combination with the nucleoside
analog ribavirin. The current gold standard is a combination
of long-acting pegylated interferon (PEG-IFN) with ribavirin
achieving a sustained virological response (SVR) with acceptable
safety profiles in 54-66% of patients. These therapies have
significantly contributed to our armamentarium against hepatitis
C virus infection. Despite this success some subgroups have
lower response rates (i.e. previous IFN non-responders, patients
with genotype 1 or cirrhosis). Moreover, the question of a
“true SVR” has been raised. Recent studies confirming
detection of residual HCV RNA using ultra-sensitive polymerase
chain reaction (PCR) based assays in patients many years after
complete clinical resolution of chronic hepatitis C raise
concerns whether these patients have actually been cured.
In this paper we review the natural history, epidemiology
and basic virology of hepatitis C. Current treatments and
long-term benefits of achieving a SVR, including the antiviral
and anti-inflammatory effects of IFN are also explored. Finally,
we review the current understanding of persistent occult viremia
in patients apparently cleared of HCV after achieving SVR
with antiviral treatment.
[Back to top]
Nematodes as Models for the Study of
the Regulation of Activity of P-glycoproteins in Multidrug
Resistance (MDR)
D. Kerboeuf and M. Riou
Alterations in drug transport are a major cause of chemotherapy
failures due to nonspecific resistance mechanisms. These mechanisms
involve several ABC transporter proteins among which the P-glycoproteins
have been the most extensively studied in vertebrates. Increased
Pgp expression and/or activity in organisms leads to resistance
to many chemically unrelated compounds and therapeutic agents.
Such resistance has been observed in cancer and in other diseases
due to infectious and parasitic pathogens. Most of the available
information on these transporters has been obtained from genetic
analyses, although useful data for understanding the cellular
mechanisms of such resistance remains limited. As resistance
affects several types of organism comparative information
on the function and activity of these cellular pumps in various
biological environments would be welcome. As such, nematodes
represent a possible model. Recent data have been obtained
for efflux function and modulation by different molecules
in these invertebrates. The observed data are summarized here
and the future of these studies is discussed.
[Back to top]
Antifungal Drugs for Systemic Mycosis: An Overview
of Mechanism of Action and Resistance
J.S. Hamdan and R.C. Hahn
Invasive fungal infections are a frequent and important
complication of modern medicine and remain important causes
of morbidity and mortality, particularly in immunocompromised
patients. In recent years, the existing antifungal armamentarium
has been increased by new drugs and/
or improvement in older drugs. In this review, we summarise
the current knowledge of the mechanisms of action and resistance
of both new and old antifungal drugs available for the treatment
of systemic mycosis. We present in addition, a summary of
the results of our studies concerning the mechanism of action
of antifungal agents and detection of in vitro resistance
of some important human fungal pathogens.
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