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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 2, February 2006
Contents
Probing for New Antiparasitic Drugs
Executive Editors: J. Golenser, Nicholas H.
Hunt and S. Sarel
Editorial Pp. 121-122
Functional Cloning as a Means to Identify
Leishmania Genes Involved in Drug Resistance Pp.
123-129
J. Clos and K. Choudhury
[Abstract]
The Use of Anticancer Drugs in Antiparasitic
Chemotherapy Pp. 131-143
M.-Q. Klinkert and V. Heussler
[Abstract]
Development of Miltefosine for the
Leishmaniases Pp. 145-151
J.D. Berman
[Abstract]
New Formulations and Derivatives of
Amphotericin B for Treatment of Leishmaniasis Pp.
153-162
J. Golenser and A. Domb
[Abstract]
Interference with Redox-Active Enzymes
as a Basis for the Design of Antimalarial Drugs Pp.
163-176
S. Rahlfs and K. Becker
[Abstract]
Drug Targets for Plasmodium falciparum:
A Post-Genomic Review/Survey Pp. 177-202
I. Yeh and R.B. Altman
[Abstract]
Antibiotics which Target the Wolbachia
Endosymbionts of Filarial Parasites: A New Strategy for Control
of Filariasis and Amelioration of Pathology Pp.203-210
K.M. Pfarr and A.M. Hoerauf
[Abstract]
General Reviews
Applications of Electron Spin Resonance and Spin Trapping
in Tropical Parasitic Diseases Pp. 211-220
C. Olea-Azar, C. Rigol, F. Mendizábal
and R. Briones
[Abstract]
Thyrotropin-Releasing Hormone Analogs Pp. 221-226
A.O. Colson and M.C. Gershengorn
[Abstract]
Multimodality Imaging of Tumor Integrin αvβ3
Expression Pp. 227-233
Xiaoyuan Chen
[Abstract]
Antioxidants as Novel Agents for Asthma Pp. 235-240
Seoung Ju Park and Yong Chul Lee
[Abstract]
Proteomics in Medicinal Chemistry Pp. 241-246
Satomi Niwayama
[Abstract]
Abstracts
[Back to top]
Editorial
Probing for Antiparasitic Drugs
Every person on earth is infected by at least several parasites.
The most dangerous parasites are transmitted by vectors and
cause the death of millions annually. In order to reduce mortality
resulting from such infections there is a need to interrupt
the life cycle of the parasites. A parasitic disease will
not be eradicated unless efforts to contain it below a “critical
mass” succeed. The critical mass may be defined as a
combination of a minimum number of infected human, infected
reservoir animals (when relevant, e.g. leishmaniasis), and
a minimum amount of vectors (e.g. Simulium in river
blindness). A failure to control the vectors and insufficient
treatment of human patients originates from the increasing
resistance of the vectors to insecticides and from parasite
drug resistance. In addition, economic considerations are
highly responsible for the prevalence of the diseases.
In this issue our aim is to consider novel and recent approaches
to chemotherapy of vector-born parasitic diseases. Recent
advances regarding the biology, physiology and biochemistry
of the parasites have led to the recognition of new targets
for chemotherapy. These targets must be specific in order
to increase the therapeutic value of the drug. Lead optimization
may help in designing new drugs such as enzyme inhibitors.
For example, cysteine proteases of various parasites could
be an important target; in malaria parasites they are involved
in hemoglobin degradation and in Leishmania parasites in digestion
within lysosomes/endosomes. A second approach to drug discovery
is based on the screening of traditional drugs. Some of these
compounds were used long before the understanding of their
mechanism of action and some are still in use despite their
unknown mechanism (e.g. quinine). A third approach aims at
improvement of existing drugs by derivatization, which enables
better transport to the target cell/organ (e.g. diamidine
derivatives against sleeping sickness) or slow release in
order to allow for sufficient stable amounts of the drug.
Despite the continuous, extensive studies being carried out,
the amount of newly approved effective anti-parasitic drugs
in the last 5 years, is frustrating and can be counted on
the fingers of one hand. A main reason for the limited success
of developing new drugs is the lack of understanding of mechanisms
of drug action which are additional to the direct anti-parasitic
effects. While it is relatively easy to examine drug effects
on in vitro cultures of the parasite, the actual
activity, efficacy and safety of drugs depend on various factors.
These include the direct anti-parasitic effect, and the effect
on immune and physiological functions. These considerations
could be demonstrated by artemisinin and its derivatives.
Artemisinin is a prodrug which is transformed to the active
derivative dihydroartemisinin (DHA). It is a common dogma
that it is active because it contains a peroxide bridge which
interacts with iron to form a reactive free radical. Despite
its accumulation in the parasitized erythrocyte its high anti-malarial
therapeutic index can not be solely attributed to its radical
activity. DHA in vitro kills bacteria, various protozoa
(e.g. Leishmania) and animal cells at μM
concentrations. However, the ID50 for malaria parasites
is lower than 1 nM. This low ID50 has been attributed
to DHA’s activity against the plasmodial SERCA (Ca-ATPase).
There are additional effects which are not anti-parasitic
but affect the fate of the malaria infected patient: DHA reduces
vascular endothelial growth factor (VEGF) which consequently
may affect the pathogenesis of in vivo infection.
Moreover, treatment with high concentrations of DHA may suppress
both humoral and cellular immune responses. Low concentrations
may stimulate T-lymphocyte cell mediated responses.
The therapeutic index of a drug would be increased if large
amounts could be targeted to the affected host organ and parasite
molecule. The outmoded former drug chloroquine was a most
valuable drug because it was accumulated in the parasitized
erythrocyte and has a specific target which is related to
hemoglobin degradation and hemozoin formation. Chloroquine
is not in use any more due to plasmodial drug resistance.
It took more than 20 years until chloroquine resistance spread
throughout all endemic areas. However, sometimes it is possible
to predict the probability of induction of drug resistance
by exposing the parasites to increasing quantities of the
drug and by using molecular markers. J. Clos and K. Choudhury
use functional cloning as a means to identify Leishmania
genes involved in drug resistance. Resistance to established
anti-leishmanial drugs is a mounting problem in high-endemicity
regions and in the context of HIV-Leishmania coinfections.
The molecular basis for clinical drug resistance is still
largely unknown. It is important, however, to identify all
relevant drug resistance markers for further drug development
and for epidemiological surveys. An elegant and powerful method
to identify such drug resistance markers without bias is functional
cloning, using cosmid-based genomic DNA libraries. The review
of Clos and Choundury discusses the merits and caveats of
this approach.
Many similarities exist between cancer cells and parasites.
A potentially lucrative starting point for the discovery of
novel drugs to combat parasites is to examine available compounds
developed against cancers for new anti-parasitic properties.
Here, M.-Q. Klinkert and V. Heussler review the use of current
and promising anti-cancer agents for the treatment of major
human parasitic diseases. The paper by J.D. Berman describes
the clinical considerations that eventually enabled the approval
of miltefosine as an anti-leishmanial drug. This may be the
best example of a successful anti-parasitic drug that originally
was planned as an anti-tumor drug. It is also the last anti-parasitic
drug that was approved for human use (2002).
The clinical treatment of leishmaniasis is based on a limited
number of drugs which are associated with adverse effects
and have already induced resistance. Amphotericin B (AmB)
is the only anti-leishmanial drug which has not induced clinical
resistance. The limiting factor in the use of AmB is its toxic
effects, mainly nephrotoxicity. The mode of action of AmB
is associated with its toxicity: it selectively binds to parasite
membrane ergosterol but also, to a lesser extent, to human
cholesterol. AmB also has immunomodulatory effects, some of
them deleterious. J. Golenser and A. Domb discuss the current
efforts to improve AmB by production of AmB aggregates in
liquid solutions, encapsulation with lipid components, and
solubilization by binding to soluble polymers. The expected
improved treatment is based on better pharmacokinetics, reduced
toxicity and an altered pattern of immune responses. Of particular
importance are the attempts to produce derivatives for oral
treatment, which will decrease costs of hospitalization and
improve applicability.
The plasmodium-erythrocyte unit is specifically sensitive
to oxidant stress that is inserted by the growing parasite,
some labile iron that is released by the parasite and may
participate in radical inducing reactions, and possibly the
host immune response. Parasite enzymes involved in antioxidant
defence are representing interesting target molecules for
rational drug development. S. Rahlfs and K. Becker summarize
the currently available data on structural, biochemical, and
functional properties of these proteins in an attempt to evaluate
and compare their potential as drug targets. I. Yeh and R.
B. Altman present a comprehensive study of anti- malarial
drugs. In their “Drug Targets for Plasmodium falciparum:
a post-genomic review/survey” they discuss drug targets
by broad biological functions and emphasize the evidence for
each drug target. The authors emphasize that the list of targets
has blossomed because of the efforts of scientists who have
taken advantage of the information provided by the sequenced
genome. The current set of drug targets is heavily weighted
toward metabolic pathways, but this may change with increased
understanding of parasite signalling mechanisms and the parasite’s
interactions with host cells.
In order to cure or alleviate a parasitic disease it is common
to use drugs that reduce parasite burden or minimize deleterious
host responses to the parasite. Another approach which could
decrease the prevalence of the diseases is to kill parasites
by infecting them with their own parasites. This kind of treatment
has been successfully used for various insect vectors. Evolution
goes in various directions - in the case of filariasis it
is possible to reduce the prevalence of the disease by using
biological agents like Bacillus thuringiensis israeliensis
(Bti) which kills the vectors. K. M. Pfarr and A. M. Hoerauf
discuss a different approach: the use of antibiotics against
Wolbachia endosymbionts of filariae. Wolbachia
are essential to the biology of filarial worms and appear
to have a major role in the development of filarial pathology.
Therefore, Wolbachia are targets for the development
of new antifilarial chemotherapy: the drugs which deplete
Wolbachia from the worm have demonstrated the feasibility
of this strategy and have provided a new chemotherapeutic
tool. Recent research shows that depleting Wolbachia
will also lessen pathology, and lessen adverse reactions to
traditional anti-filarial drugs.
It is impossible to include in one issue all of the new approaches
to parasite chemotherapy but we present here a selection of
reviews which could demonstrate new approaches that might
lead to better treatment of parasitic diseases.
Jacob Golenser
The Hebrew University of Jerusalem
Jerusalem
Israel
E-mail: golenser@md.huji.ac.il
Nicholas H. Hunt
University of Sydney
Sydney
Australia
Shalom Sarel
The Hebrew University of Jerusalem
Israel
[Back to top]
Functional Cloning as a Means to Identify
Leishmania Genes Involved in Drug Resistance
J. Clos and K. Choudhury
Resistance to anti-leishmanial drugs is a mounting problem
in high-endemicity regions of South Asia and, potentially,
in the context of HIV-Leishmania coinfections in
Southern Europe. The molecular basis for clinical drug resistance
is still largely unknown. It is important, however, to identify
all relevant drug resistance markers for further drug development
and for epidemiological surveys. An elegant and powerful method
to identify such drug resistance markers without bias is functional
cloning, using cosmid-based genomic DNA libraries. This review
discusses the merits and caveats of this approach.
[Back to top]
The Use of Anticancer Drugs in Antiparasitic
Chemotherapy
M.-Q. Klinkert and V. Heussler
Many similarities exist between cancer cells and parasites.
A potentially lucrative starting point for the discovery of
novel drugs to combat parasites is to examine available compounds
developed against cancer for antiparasitic properties. Here,
we review the use of current and promising anticancer agents
for treating major human parasitic diseases.
[Back to top]
Development of Miltefosine for the Leishmaniases
J.D. Berman
The leishmaniases consist of visceral and cutaneous syndromes
present in > 30 endemic regions of the world. Miltefosine
(hexadecylephosphocholine) is the first oral agent that is
effective and tolerated for both visceral and cutaneous disease
in several endemic regions, and represents a major advance
in the treatment of these diseases.
[Back to top]
New Formulations and Derivatives of Amphotericin
B for Treatment of Leishmaniasis
J. Golenser and A. Domb
The clinical treatment of leishmaniasis is based on a limited
number of drugs, which are associated with adverse effects
and have already induced resistance. Amphotericin B (AmB),
a polyene antibiotic produced by Streptomyces sp, is the only
anti-leishmanial drug which has not induced clinical resistance
since its discovery in 1956. The limiting factor in the use
of AmB is its toxic effects, mainly nephrotoxicity. The maximal
dose of AmB for human use is 1.5 mg/kg which sometimes is
not sufficient for cure. The mode of action of AmB is associated
with its toxicity: it selectively binds to parasite membrane
ergosterol but also, to a lesser extent, to human cholesterol.
Apart from this mechanism, AmB has immunomodulatory effects,
some of them are deleterious. Reduction of the toxic effects
by using lipid formulations allows the infusion of higher
doses of AmB. Unfortunately, these formulations are relatively
expensive and therefore out of reach for patients in need,
in the endemic areas. All the existing formulations are given
parenterally, which has obvious disadvantages; most important
is the need for hospitalization or multiple visits in the
clinic. The current efforts to improve AmB are directed at
the production of AmB aggregates in liquid solutions, encapsulation
with lipid components, and solubilization by binding to soluble
polymers. The expected improved treatment resulting from use
of the new formulations is based on better pharmacokinetics,
reduced toxicity originating from slow release, targeting
to the infected organ and an altered pattern of immune responses
(related to AmB). Of particular importance are the attempts
to produce derivatives for oral treatment, which will decrease
costs of hospitalization and improve applicability for children
and the elderly population.
[Back to top]
Interference with Redox-Active Enzymes as
a Basis for the Design of Antimalarial Drugs
S. Rahlfs and K. Becker
Antimalarial drugs are urgently and continuously required.
Parasite enzymes involved in antioxidant defence represent
interesting target molecules for rational drug development.
Here we summarize the currently available data on structural,
biochemical, and functional properties of these proteins in
an attempt to evaluate and compare their potential as drug
targets.
[Back to top]
Drug Targets for Plasmodium falciparum:
A Post-Genomic Review/Survey
I. Yeh and R.B. Altman
Over 300 million cases of malaria each year cause significant
morbidity and mortality. Growing drug-resistance among the
Plasmodia that cause malaria motivates the development of
additional anti-malarial drugs. This review summarizes the
current state of knowledge about potential drug targets for
malaria. The recently sequenced malaria genome data clarifies
parasite metabolic pathways, and more metabolic targets have
been identified.
[Back to top]
Antibiotics which Target the Wolbachia
Endosymbionts of Filarial Parasites: A New Strategy for Control
of Filariasis and Amelioration of Pathology
K.M. Pfarr and A.M. Hoerauf
Wolbachia endosymbionts of filariae are targets
for the development of new antifilarial chemotherapy. Doxycycline
to deplete Wolbachia from the worm has demonstrated
the feasibility of this strategy and has provided a new chemotherapeutic
tool. Recent research shows that depleting Wolbachia
will also lessen pathology, and lessen adverse reactions to
traditional antifilarial drugs.
[Back to top]
Applications of Electron Spin Resonance and
Spin Trapping in Tropical Parasitic Diseases
C. Olea-Azar, C. Rigol, F. Mendizábal
and R. Briones
Free radicals may be reaction intermediates in biological
systems in more situations than are presently recognized.
However, progress in detecting such species by Electron Spin
Resonance (ESR) has been relatively slow. ESR is a very sensitive
technique for free radical detection and characterization.
It can be used to investigate very low concentrations of radicals
provided that they are stable enough for their presence to
be detected. For unstable radicals special techniques have
to be employed. One of these methods is called Spin Trapping.
Parasitic diseases in tropical and subtropical areas constitute
a major health and economic problem. The range of antiparasitic
drugs varies widely in structural complexity and action at
the subcellular and molecular levels. However, a number of
these drugs are thought to exert their action by generating
free radicals. Most of the free radical producing drugs used
against parasites are: quinones, naphtoquinones, quinone-imines,
aminoquinolines, N-oxides and nitroheterocyclic compounds.
This review summarizes some of the more relevant achievements
of ESR and Spin Trapping applications in parasitic diseases
studies. The use of ESR spectroscopy to obtain relevant information
about free radical characterization and the analysis of the
mechanisms of action of drugs involved in several parasitic
diseases is also presented.
[Back to top]
Thyrotropin-Releasing Hormone Analogs
A.O. Colson and M.C. Gershengorn
Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide)
regulates the activity of cells in the anterior pituitary
and within the central and peripheral nervous systems. TRH,
which has been the subject of much research over the past
three decades, exerts its effects by acting through class
A G-protein coupled receptors. The recent discovery of a second
receptor subtype has generated an interest in the discovery
of receptor subtype-selective TRH analogs. In this review,
we describe advances in the development of TRH analogs and
in the understanding of their mechanism of interaction with
TRH receptors. We also describe the recent breakthrough in
the identification of analogs that bind selectively at TRH-R2.
[Back to top]
Multimodality Imaging of Tumor Integrin αvβ3
Expression
Xiaoyuan Chen
Most solid tumors are angiogenesis dependent. Anti-angiogenic
pharmaceuticals that inhibit the growth of new blood vessels
offer considerable promise as anti-cancer agents. With increasing
numbers of anti-angiogenic drugs in clinical trials, there
is an urgent need for detailed characterization of the heterogeneity
of tumor vasculature and dissection of the complex network
of mechanisms that control tumor angiogenesis. Non-invasive
molecular imaging will play a key role in individualized anti-angiogenic
therapy based upon molecular features of the new blood vessel
growth. Integrin αvβ3
, which binds several ligands via an RGD tripeptide sequence,
is uniquely expressed in tumor vasculature and aggressive
tumor cells, making it a potential target for anti-angiogenic
interventions. This review highlights some recent advances
in multimodality imaging of tumor integrin expression with
emphasis on positron emission tomography (PET).
[Back to top]
Antioxidants as Novel Agents for Asthma
Seoung Ju Park and Yong Chul Lee
Oxidative stress plays an important role in the pathogenesis
of asthma. Recently several investigators have studied the
effects of a variety of antioxidants on asthma. Antioxidants,
including L-2-oxothiazolidine-4-carboxylic acid, reduce airway
inflammation and hyper-responsiveness of asthma and may be
novel therapeutic agents for asthma.
[Back to top]
Proteomics in Medicinal Chemistry
Satomi Niwayama
Proteomics is becoming an important research area for studying
protein expression patterns induced by different external
stimuli. An important aspect of proteomics is to identify
and quantify proteins. Many new technologies and techniques
have been developed in this field and have been applied to
various aspects of drug discovery.
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