| Recent
Patents on Anti-Infective Drug Discovery
ISSN: 1574-891X
Recent Patents on Anti-Infective
Drug Discovery
Volume 1, Number 1, January 2006
Contents
Patented HIV-1 Integrase Inhibitors (1998-2005) Pp.1-15
Philippe Cotelle
[Abstract] [Full
Text Article]
Recent Progress in Pharmacological Research of Antioxidants
in Pathological Conditions: Cardiovascular Health Pp.17-31
Victor M. Victor, Kenneth J. McCreath & Milagros Rocha
[Abstract] [Full
Text Article]
Promising Drugs Against Tuberculosis Pp.33-44
Marcus Vinícius Nora de Souza
[Abstract] [Full
Text Article]
Recent Advances in Flavivirus Antiviral Drug Discovery and
Vaccine Development Pp.45-55
Debashish Ray & Pei-Yong Shi
[Abstract] [Full
Text Article]
C5a, a Therapeutic Target in Sepsis Pp.57-65
Ren-Feng Guo & Peter A. Ward
[Abstract] [Full
Text Article]
An Insight on the Leading HIV Entry Inhibitors Pp.67-73
Ana Salomé Veiga, Nuno C. Santos & Miguel
Agusto Rico Botas Castanho
[Abstract] [Full
Text Article]
Current Status and Future of Antifungal Therapy for Systemic
Mycoses Pp.75-84
Joshua D. Nosanchuk
[Abstract] [Full
Text Article]
Pegylated Interferons for the Treatment of Chronic Hepatitis
B Pp.85-94
Chun-Jen Liu & Jia-Horng Kao
[Abstract] [Full
Text Article]
Attack on the Scourge of Tuberculosis: Patented Drug Targets
Pp.95-106
Reena Vohra, Meetu Gupta, Rekha Chaturvedi & Yogendra
Singh
[Abstract] [Full
Text Article]
Inhibition of HIV-1 Entry into Cells Pp.107-112
Karen Florence Thomas Copeland
[Abstract] [Full
Text Article]
Anti-Infective Quinone Derivatives of Recent Patents Pp.113-125
Junko Koyama
[Abstract]
[Full
Text Article]
Patent Annotations
Pp.127-133
Patent Selections
Pp.135-145
Abstracts
[Back to top]
Patented HIV-1 Integrase Inhibitors (1998-2005)
Philippe Cotelle
[Full Text Article]
Combination therapy, comprising at least three anti-human
immunodeficiency virus (anti-HIV) drugs, has become the standard
treatment of AIDS. Since 1996, highly active antiretroviral
therapy (HAART) was designed to rapidly control HIV replication.
It has had a significant impact on patient health and progression
of AIDS in developed countries but its success has not been
complete. HAART strategy still suffers from issues of patient
compliance, cost, deleterious side effects and emerging drug
resistance. Therefore it is logical to look for agents that
inhibit different viral targets. In addition to the fusion,
reverse transcription and protein formation processes, the
HIV replicative cycle offers various other events that can
be considered as potential targets for chemotherapeutic intervention.
Amongst them integration is a key step and integrase (IN),
one of the three viral enzymes, has been rapidly identified
as a rational target for many years. To date, four molecules
have entered in clinical trials. The present article reviews
the increasing number of patents on small molecule HIV-1 integrase
inhibitors in the 1998-2005 period, from the pioneer ones
(discovery of selective strand transfer inhibitors) to the
last patents including the actual molecules under clinical
trials.
[Back to top]
Recent Progress in Pharmacological Research of Antioxidants
in Pathological Conditions: Cardiovascular Health
Victor M. Victor, Kenneth J. McCreath & Milagros
Rocha
[Full Text Article]
Antioxidants are essential, and are involved in several important
biological processes such as immunity, protection against
tissue damage, reproduction, growth and development. Antioxidants
preserve adequate function of cells against homeostatic disturbances
such as those caused by septic shock, aging and, in general,
processes involving oxidative stress. Each year, many scientific
articles are published describing the pharmacological and
biological properties of antioxidants. This review article
compiles recent findings on these properties, focusing mainly
on the anti-inflammatory properties of antioxidants in different
pathological areas, such as cardiovascular damage and sepsis.
In relation to this process, this review focuses on the involvement
of reactive oxygen and nitrogen species. Finally, the protective
role of antioxidants against homeostatic disturbances such
as those caused by endotoxin toxicity and cardiovascular damage,
their potential clinical use, and the effects on the redox
state of immune cells are discussed.
[Back to top]
Promising Drugs Against Tuberculosis
Marcus Vinícius Nora de Souza
[Full Text Article]
Tuberculosis (TB) is an important public health problem worldwilde
due to AIDS epidemic, the advent of multidrug resistant strains
(MDR) and the lack of new drugs in the market. TB is responsible
for almost 3 millions deaths each year. According to WHO (World
Health Organization), which declared tuberculosis a global
health emergency in 1993, tuberculosis, without a coordinated
control effort, will infect an estimated 1 billion people
by 2020, killing 70 million. In spite of this problem, there
is a lack of development of new TB drugs. For example, it
has been nearly 35 years since the introduction of a new class
of compounds for the treatment of TB. Thus, there is an urgent
need for new drugs to fight against this disease. Considering
that, this review aims promising drug candidates that are
in development against TB.
[Back to top]
Recent Advances in Flavivirus Antiviral Drug Discovery
and Vaccine Development
Debashish Ray & Pei-Yong Shi
[Full Text Article]
Many flaviviruses, including yellow fever virus, dengue virus,
Japanese encephalitis virus, tick-borne encephalitis virus,
and West Nile virus, are globally important human pathogens.
Despite an emergence and resurgence of flavivirus-mediated
disease, specific therapies are not yet available; however,
significant progress has been made toward the prevention and
treatment of flavivirus infections. In this article we review
recent advances made in the areas of (i) flavivirus vaccine
development, and (ii) antiflavivirus drug discovery reported
in literature and patents, and highlight strategies used in
these investigations.
[Back to top]
C5a, a Therapeutic Target in Sepsis
Ren-Feng Guo & Peter A. Ward
[Full Text Article]
The complement activation product, C5a, is a potent inflammatory
peptide with a broad spectrum of biological functions. Plasma
levels of C5a are increased in sepsis, accompanied by increased
content of C5a receptor (C5aR) in various organs. In the mouse
and rat models of sepsis (cecal ligation and puncture, CLP),
C5a blockade by anti-C5a antibody, anti-C5aR antibody or use
of a C5aR antagonist (C5aRa) significantly improved survival
in CLP animals. C5a blockade in sepsis attenuated the systemic
inflammatory response syndrome (SIRS) by reducing plasma levels
of IL-6 and decreasing bacteria counts in blood and organs.
Anti-C5a treatment in CLP rodents markedly attenuated sepsis-induced
defects in the coagulation/fibrinolytic system, while liver
and kidney functions were remarkably preserved in contrast
to CLP animals not receiving anti-C5a in which multi-organ
failure occurs. In CLP rats treated with anti-C5a, thymus
atrophy was diminished and thymocyte apoptosis was inhibited.
Defective neutrophil functions (chemotaxis, phagocytosis,
respiratory burst) caused by sepsis were significantly improved
in CLP rats treated with anti-C5a. These data suggest during
CLP-induced sepsis C5a has very harmful consequences and that
its blockade might be a promising therapeutic strategy for
the treatment of humans with sepsis. This review will summarize
the beneficial effects of anti-C5a treatment in the rodent
model of sepsis and will introduce the most recent patents
on this line of research.
[Back to top]
An Insight on the Leading HIV Entry Inhibitors
Ana Salomé Veiga, Nuno C. Santos & Miguel
Agusto Rico Botas Castanho
[Full Text Article]
The main strategies nowadays to fight AIDS rely on chemical
therapy to inhibit the reverse transcriptase or protease of
HIV. However, a synthetic 36 amino-acids peptide that blocks
the entry of the virus in the target cells (enfuvirtide) has
recently reached approval for clinical application. This molecule
may probably be just the leader of a new generation of drugs
that is about to emerge to interrupt the first step in the
HIV life cycle, i.e. preventing the virus from actually entering
cells. This paper reviews the enfuvirtide path from clinical
trials to the attempts to detail its molecular-level mode
of action. It is commonly accepted that this peptide would
block the fusion between viral and cell plasma membrane through
binding to the N-terminal heptad repeat (NHR) region of the
viral protein gp41. However, there has been growing evidence
that this model of action may be unrealistic, the action of
enfuvirtide being more complex and diverse than initially
thought. Membrane-assisted local concentration increase and
interference with gp120/co-receptor docking may also contribute
for the inhibitory action of the peptide. Selected HIV-entry
inhibitors on clinical trials are presented to characterize
the future drugs in the market in this class.
[Back to top]
Current Status and Future of Antifungal Therapy for Systemic
Mycoses
Joshua D. Nosanchuk
[Full
Text Article]
Since the 1950s there has been an increase in the incidence
of invasive fungal disease. The first successful systemically
administered antifungal drug, amphotericin B, was introduced
in the 1950s and, until very recently, was considered the
best therapeutic drug for severe mycoses. The development
of new antifungals to treat systemic disease has been slow
compared to that of antibacterial compounds, with the introduction
of only a single new class of drugs over the past 20 years.
This review discusses the antifungal drugs that are clinically
in use and summarizes interesting new applications and patents
from the US Patent and Trademark Office.
[Back to top]
Pegylated Interferons for the Treatment of Chronic Hepatitis
B
Chun-Jen Liu & Jia-Horng Kao
[Full
Text Article]
Five drugs are approved for the treatment of chronic hepatitis
B: conventional interferon (IFN) alfa, lamivudine, adefovir
dipivoxil, pegylated interferon (peginterferon) alfa-2a and
entecavir. Conventional IFN monotherapy has a narrow range
of efficacy, should be administered subcutaneously and is
commonly associated with adverse effects. Lamivudine is cheaper
and well tolerated, but the virological response may not be
durable and prolonged lamivudine treatment is commonly associated
with the emergence of drug-resistant mutants. Adefovir dipivoxil
is potent but with nephrotoxicity at higher doses. Entecavir
is active against both lamivudine- and adefovir dipivoxil-naïve
and -resistant HBV, however, its long-term efficacy remains
to be evaluated. Peginterferon alfa-2a has recently been shown
to be superior to conventional IFN and lamivudine in the treatment
of both HBeAg-positive and -negative chronic hepatitis B.
By using peginterferon alfa-2a monotherapy, the overall virological
and serological responses are around 30%-44%. However, peginterferon
alfa-2a in combination with lamivudine does not improve the
results at the end of follow-up. Adverse effects are usually
tolerable and comparable with conventional IFN. Similar efficacy
of peginterferon alfa-2b has also been demonstrated in HBeAg-positive
chronic hepatitis B. These observations suggest an important
and even a primary role of peginterferon alfa in the treatment
of chronic HBV infection.
[Back to top]
Attack on the Scourge of Tuberculosis: Patented Drug Targets
Reena Vohra, Meetu Gupta, Rekha Chaturvedi & Yogendra
Singh
[Full Text Article]
Tuberculosis is one of the most devastating bacterial diseases,
with increasing rates of morbidity and mortality, despite
the presence of effective chemotherapy and Bacillus-Calmette-Guerin
(BCG) vaccine. The success of Mycobacterium tuberculosis
lies in its ability to spread by aerosol droplets, evade the
host immune system and to persist in pulmonary granulomas.
The advancement in the field of molecular and cellular microbiology
and the availability of transcriptome and proteome data of
M. tuberculosis have aided in understanding the pathogenesis
of this organism for developing more effective drugs. The
current strategy of drug design is to identify gene products,
which are essential for survival and virulence. To date, several
gene products of mycobacteria, ranging from proteins involved
in cell wall synthesis to energy generation and from entry
into host to persistence, have been shown to be essential
for the survival or virulence of M. tuberculosis.
These proteins and their associated pathways are considered
as promising drug targets against M. tuberculosis
and several of these have been patent protected. Herein, we
enlist drug targets against M. tuberculosis for which
patents have been filed and issued during the last ten years.
The significance of these drug targets in the development
of drug is also discussed. This review presents a comprehensive
account of the pivotal information for drug discovery and
drug design to all researchers involved in tuberculosis research.
[Back to top]
Inhibition of HIV-1 Entry into Cells
Karen Florence Thomas Copeland
[Full Text Article]
Treatments for HIV-1 include drugs which act to inhibit specific
steps in the virus life cycle such as reverse transcription
and viral maturation. In 1995 breakthroughs were made in our
understanding of the entry of HIV-1 into cells. HIV-1 was
shown to use, in addition to the CD4 receptor, chemokine co-receptors,
primarily CCR5 and CXCR4, for entry into CD4+ T
cells and macrophages. These discoveries have provided another
target for the treatment of HIV-1 infection. Drugs developed
to block HIV-1 entry include CD4 receptor inhibitors, chemokine
receptor inhibitors and inhibitors of attachment and membrane
fusion. These drugs may add a further treatment for HIV-1
infection along with protease inhibitors and reverse transcription
inhibitors. Several of the entry inhibitors are currently
being used in clinical trials and demonstrate efficacy in
vivo. In this review, the entry blocking drugs that have
recently been patented, their mode of action in inhibiting
HIV-1 and their efficacy in clinical trials will be discussed.
[Back to top]
Anti-Infective Quinone Derivatives of Recent Patents
Junko Koyama
[Full Text Article]
Quinones are important naturally occurring pigments widely
distributed in nature and are well known to demonstrate various
physiological activities as antimicrobial and anticancer compounds.
This review will focus on the preparation, therapeutic application,
and administration of several benzoquinones, naphthoquinones,
and anthraquinones having anti-infective, e.g. antiviral and
antibacterial activities, in recent patents.
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