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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 9, 2008
Contents
Trypanosomiais and Leishmaniasis “Recent Development
in the Chemotherapy of Infectious Diseases caused by Parasitic
Protozoa”
Executive Editor: Wanderley de Souza
Editorial: 821
An Introduction to the Structural Organization of Parasitic
Protozoa Pp. 822-838
W. de Souza
[Abstract] [Purchase
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Mitochondrion of Protozoan Parasite Emerges as Potent
Therapeutic Target: Exciting Drugs are on the Horizon
Pp. 839-846
N. Sen and H.K. Majumder
[Abstract] [Purchase
Article]
Kinetoplast as a Potential Chemotherapeutic Target
of Trypanosomatids Pp. 847-854
M.C.M. Motta
[Abstract] [Purchase
Article]
The Plastid-Like Organelle of Apicomplexan Parasites
as Drug Target Pp. 855-871
J. Wiesner, A. Reichenberg, S. Heinrich, M.
Schlitzer and H. Jomaa
[Abstract] [Purchase
Article]
The Hydrogenosome as a Drug Target Pp.
872-881
M. Benchimol
[Abstract] [Purchase
Article]
The Acidocalcisome as a Target for Chemotherapeutic
Agents in Protozoan Parasites Pp. 882-888
R. Docampo and S.N.J. Moreno
[Abstract] [Purchase
Article]
Drugs Targeting Parasite Lysosomes Pp.
889-900
P.S. Doyle, M. Sajid, T. O’Brien, K. DuBois,
J.C. Engel, Z.B. Mackey and S. Reed
[Abstract] [Purchase
Article]
Fatty Acid Synthesis in Protozoan Parasites: Unusual
Pathways and Novel Drug Targets Pp. 901-916
C.D. Goodman and G.I. McFadden
[Abstract] [Purchase
Article]
Targeting the Cell Cycle in the Pursuit of Novel
Chemotherapies Against Parasitic Protozoa Pp.
917-924
K.M. Grant
[Abstract] [Purchase
Article]
Ultrastructural Alterations in Organelles of Parasitic
Protozoa Induced by Different Classes of Metabolic Inhibitors
Pp. 925-938
J.C.F. Rodrigues and W. de Souza
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Abstracts
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Editorial: Trypanosomiais and Leishmaniasis
“Recent Development in the Chemotherapy of Infectious
Diseases caused by Parasitic Protozoa”
The high impact of diseases caused by parasitic protozoa shortens
working capacity, causing premature disability, shortening
of life quality and expectancy of individuals, leading to
economical and social losses. In this issue of Current Pharmaceutical
Design several articles, written by colleagues with a major
contribution on the area, deal with drugs that interfere with
specific structures/organelles of the most important protozoa.
In the first article, W. de Souza [1] makes a brief review
on the structural organization of parasitic protozoa, pointing
out the main structures and organelles that make them very
special as eukaryotic cells.
In the second article, N. Sen and H.M. Majumder [2] review
the available information on the mitochondrion of protozoa
and its potentiality as drug target.
The third article, by M.C.M. Motta [3] analyses the kinetoplast,
a defining characteristic of the order Kinetoplastida, in
which the Trypanosomatidae family is included, and its potentiality
as drug target.
In the fourth article J. Wiesner, A. Reichenberg, S. Heinrich,
M. Schlitzer and H. Jomma [4] review the new information available
on the plastid-like organelle found in apicomplexan parasites.
The fifth article by M. Benchimol [5] deals with the hydrogenosome,
an organelle characteristic of trichomonads and validated
as drug target in view of peculiarities of its metabolic role.
The sixth article by R.Docampo and S.N.J. Moreno [6] brings
an up to date view of the acidocalcisome, an organelle described
and characterized in recent years in a large number of pathogenic
protozoa.
In the seventh article P.S. Doyle, M. Sajid, T. O’Brien,
K. DuBois, J.C. Engel, Z.B. Mackey and S. Reed [7] review
information on the lysosome. Fifty years after its first description,
this organelle, has pivotal role in several biological functions.
The eight article by C.D. Goodeman and G.I. McFadden [8] review
the available information on a new and interesting drug target,
the fatty acid biosynthesis pathway.
In the ninth article, K.M. Grant [9] covers the present day
information on the cell cycle of pathogenic protozoa and the
potential of its steps as drug targets.
Finally, J.C.F.Rodrigues and W. de Souza [10] make a review
on the potentiality of electron microscopy for the analysis
of the effect of drugs on the structural organization of pathogenic
protozoa.
References
[1] de Souza W. An Introduction to the Structural Organization
of Parasitic Protozoa. Curr Pharm Des 2008; 14(9): 822-838.
[2] Sen N, Majumder HK. Mitochondrion of Protozoan Parasite
Emerges as Potent Therapeutic Target: Exciting Drugs are on
the Horizon. Curr Pharm Des 2008; 14(9): 839-846.
[3] Motta MCM. Kinetoplast as a Potential Chemotherapeutic
Target of Trypanosomatids. Curr Pharm Des 2008; 14(9): 847-854.
[4] Wiesner J, Reichenberg A, Heinrich S, Schlitzer M, Jomaa
H. The Plastid-Like Organelle of Apicomplexan Parasites as
Drug Target. Curr Pharm Des 2008; 14(9): 855-871.
[5] Benchimol M. The Hydrogenosome as a Drug Target. Curr
Pharm Des 2008; 14(9): 872-881.
[6] Docampo R, Moreno SNJ. The Acidocalcisome as a Target
for Chemotherapeutic Agents in Protozoan Parasites. Curr Pharm
Des 2008; 14(9): 882-888.
[7] Doyle PS, Sajid M, O’Brien T, DuBois K, Engel JC,
Mackey ZB, Reed S. Drugs Targeting Parasite Lysosomes. Curr
Pharm Des 2008; 14(9): 889-900.
[8] Goodman CD, McFadden GI. Fatty Acid Synthesis in Protozoan
Parasites: Unusual Pathways and Novel Drug Targets. Curr Pharm
Des 2008; 14(9): 901-916.
[9] Grant KM. Targeting the Cell Cycle in the Pursuit of Novel
Chemotherapies Against Parasitic Protozoa. Curr Pharm Des
2008; 14(9): 917-924.
[10] Rodrigues JCF, de Souza W. Ultrastructural Alterations
in Organelles of Parasitic Protozoa Induced by Different Classes
of Metabolic Inhibitors. Curr Pharm Des 2008; 14(9): 925-938.
Wanderley de Souza
Laboratório de Ultraestrutura Celular Hertha Meyer
Instituto de Biofísica Carlos Chagas Filho
Universidade Federal do Rio de Janeiro
CCS-Bloco G, 21941-900
Rio de Janeiro
Brasil
E-mail: wsouza@biof.ufrj.br
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An Introduction to the Structural Organization of Parasitic
Protozoa
W. de Souza
As eukaryotic cells, protozoa present a classical structural
organization where most of the structures and organelles typical
of mammalian cells are found. However, even for usual organelles
these organisms present structural diversity. In addition,
some of the protozoa structures, such as the mitochondria,
peroxisomes and even the Golgi complex, are not observed.
On the other hand, new organelles such as the hydrogenosomes,
mitosomes, Apicoplast, kinetoplast, glycosomes (specialized
peroxisomes), rhoptries, micronemes and dense granules, are
characteristic features of some protozoa. Also, several unusual
cytoskeletal structures, some of them made of yet uncharacterized
proteins, are seen in these eukaryotic microorganisms. Further
characterization of these structures indicates that they con-tain
special enzymes involved in distinct metabolic pathways making
them potential targets for the development of new anti parasite
drugs.
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Mitochondrion of Protozoan Parasite Emerges as Potent
Therapeutic Target: Exciting Drugs are on the Horizon
N. Sen and H.K. Majumder
Chemotherapy is the primary means of treating protozoan parasitic
infections. A problem for chemotherapy is to find a novel
and potential molecule in protozoa, which could be exploited
as drug target. To reach this goal, mitochondrion of protozoa
can be considered as the most valuable and potential organelle
because of its unique structure and function compared to their
natural host habitat. In fact, the respiratory systems of
parasitic protozoa typically show greater diversity in electron
pathways than do their host animals. These unique aspects
of electron transport chain (ETC) complexes and their related
enzymes represent promising targets for chemotherapy. A cytochrome
independent Alternative Oxidase (AOX) in parasites is a leading
drug target. Topoisomerases play key functions in replication
and organization of kDNA, which is present in a specialized
region of unique mitochondria known as kinetoplast. They are
considered as potential targets for anti-parasitic drugs.
Moreover, a novel pathway of type II Fatty acid synthesis
in mitochondria of trypanoso-matids provides a new array of
inhibitors that could be effective against these parasites.
Recent studies on the emergence of drug resistance severely
limit the arsenal of available drugs against protozoan parasites.
Particularly, mutations of cytochrome b gene of ETC or changes
in iron homeostasis by mitochondrial enzyme aconitase alter
sensitivity of MDR1 and regulate resistance level to anti-parasitic
drugs. This review summarizes recent state of our knowledge
and understanding of the action of various therapeutically
applied sub-stances on mitochondria and their potential application
in the future.
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Kinetoplast as a Potential Chemotherapeutic Target
of Trypanosomatids
M.C.M. Motta
Many trypanosomatid protozoa, such as those belonging to the
Trypanosoma and Leishmania genera cause
serious diseases to man. Such parasites present an unusual
feature, a mitochondrial DNA arranged in catenated circles,
known as kinetoplast DNA (kDNA). The replication of kDNA network
is a complex process, which involves many proteins. Some of
them are classified as topoisomerases and play essential biological
roles, not only on kDNA synthesis, but also in the dynamics
of the network topology, constituting the main target for
drugs in kinetoplast. DNA binding drugs are also reported
as chemotherapeutic agents against trypanosomatid infections.
This review summarizes what is known about kinetoplast as
a potential chemotherapeutic target for trypanosomatid protozoa.
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The Plastid-Like Organelle of Apicomplexan Parasites
as Drug Target
J. Wiesner, A. Reichenberg, S. Heinrich, M.
Schlitzer and H. Jomaa
Apicomplexan parasites infectious to humans include Plasmodium
spp., Babesia spp., Toxoplasma gondii, Cryptosporidium
spp., Isospora belli and Cyclospora cayetanensis.
With exception of Cryptosporidium spp., these parasites
possess a non-photosynthetic plastid-like organelle called
apicoplast. The apicoplast possesses a small circular genome
and harbours prokaryotic-type biochemical pathways. As the
most important metabolic functions, the mevalonate independent
1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid synthesis
and the type II fatty acid synthesis system are operative
inside the apicoplast. Classical antibacterial drugs such
as cipro-floxacin, tetracycline, doxycycline, clindamycin
and spiramycin inhibit the apicoplast-located gyrase and translation
machinery, respectively, and are currently used in the clinic
for the treatment of infections with apicomplexan parasites.
As an inhibitor of isoprenoid synthesis, fosmidomycin was
proven to be effective against acute P. falciparum
malaria in clinical phase II studies. Triclosan, an inhibitor
of fatty acid synthesis, was active in a malaria mouse model.
In vitro antimalarial activity was shown for inhibitors
of peptide deformylase and the import of apicoplast-targeted
proteins. Work on various other inhibitors of apicoplast-located
biochemical processes is ongoing.
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The Hydrogenosome as a Drug Target
M. Benchimol
Hydrogenosomes are spherical or slightly elongated organelles
found in non-mitochondrial organisms. In Trichomonas
hydrogenosomes measure between 200 to 500 nm, but under drug
treatment they can reach 2 µm. Like mitochondria hydrogenosomes:
(1) are surrounded by two closely apposed membranes and present
a granular matrix: (2) divide in three different ways: segmentation,
partition and the heart form; (3) they may divide at any phase
of the cell cycle; (4) produce ATP; (5) participate in the
metabolism of pyruvate formed during glycolysis; (6) are the
site of molecular hydrogen formation; (7) present a relationship
with the endoplasmic reticulum; (8) incorporate calcium; (9)
import proteins post-translationally; (10) present cardiolipin.
However, there are differences, such as: (1) absence of genetic
material, at least in trichomonas; (2) lack a respiratory
chain and cytochromes; (3) absence of the F0-
F1 ATPase; (4) absence of
the tricarboxylic acid cycle; (5) lack of oxidative phosphorylation;
(6) presence of peripheral vesicles. Hydrogenosomes are considered
an excellent drug target since their metabolic pathway is
distinct from those found in mitochondria and thus medicines
directed to these organelles will probably not affect the
host-cell. The main drug used against trichomonads is metronidazole,
although other drugs such as β-Lapachone,
colchicine, Taxol, nocodazole, griseofulvin, cytochalasins,
hydroxyurea, among others, have been used in trichomonad studies,
showing: (1) flagella internalization forming pseudocyst;
(2) dysfunctional hydrogenosomes; (3) hydrogenosomes with
abnormal sizes and shapes and with an electron dense deposit
called nucleoid; (4) intense autophagy in which hydrogenosomes
are removed and further digested in lysosomes.
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The Acidocalcisome as a Target for Chemotherapeutic
Agents in Protozoan Parasites
R. Docampo and S.N.J. Moreno
Acidocalcisomes are acidic organelles rich in calcium and
phosphorus that have been conserved from bacteria to man.
In parasitic protozoa acidocalcisomes possess enzymes that
are absent or different from their mammalian counterparts
and could be potential targets for chemotherapy, such as the
vacuolar proton translocating pyrophosphatase, and the soluble
inorganic pyrophosphatase, both of which are inhibited by
pyrophosphate analogs (bisphosphonates). In addition, a number
of drugs, including bisphosphonates, and diamidines appear
to accumulate in these organelles and/or induce an increase
in their numbers. The mechanism of action of bisphosphonates,
however, is by inhibition of the isoprenoid pathway and more
specifically the prenyl diphosphate synthases.
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Drugs Targeting Parasite Lysosomes
P.S. Doyle, M. Sajid, T. O’Brien, K. DuBois,
J.C. Engel, Z.B. Mackey and S. Reed
Lysosomes were first described as vacuolar structures containing
various hydrolytic enzymes at acidic pH. Subsequent studies
revealed that the lysosome/vacuolar system is complex and
composed of distinct membrane-enclosed vesicles including
endosomes, primary and mature lysosomes, autophagic vesicles,
residual bodies, multivesicular bodies, and digestive lysosomes.
Lysosomes express a battery of hydrolytic enzymes including
proteases, acid phosphatases, glycosidases, and lipases.
Parasitic protozoa also possess complex intracellular lysosomes/endosomes/vesicles
involved in digestion, transport and recycling of molecules
similar to those of mammalian cells. Unique characteristics
are ascribed to lysosomes of different parasites and may even
differ between parasite stages. Transport of hydrolases and
proteins to parasite lysosomes is directed either from the
Golgi complex via endosomal vesicles or from endocytic
vesicles originated in the cell surface. Inhibition of lysosomal
proteases demonstrated that different proteolytic machineries
catabolize distinct classes of proteins, and this selectivity
may be exploited for the development of effective antiparasitic
drugs. This review describes lysosomal molecules that are
either validated or potential drug targets for Chagas’
disease, sleeping sickness, leishmaniasis, toxoplasmosis,
malaria, amebiasis, and giardiasis.
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Fatty Acid Synthesis in Protozoan Parasites: Unusual
Pathways and Novel Drug Targets
C.D. Goodman and G.I. McFadden
Fatty acid biosynthesis pathways in protozoan parasites are
reviewed with a view to targeting this metabolism for drug
therapy. The type II fatty acid biosynthesis pathways derived
from bacteria in protozoan relict plastids and mitochondria
are examined in different groups with emphasis on apicomplexa.
The suitability of different enzymes from the type II fatty
acid biosynthesis pathway for drug intervention, and the state-of-play
with known and potential inhibitors is explored. The type
I acid biosynthesis pathways that occur in select protozoan
parasites and their potential for inhibition using anti-tumour
and obesity management compounds currently in development
are also examined. Pathways used by parasites to scavenge
and modify host lipids are also described briefly and their
potential for therapeutics discussed.
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Targeting the Cell Cycle in the Pursuit of Novel Chemotherapies
Against Parasitic Protozoa
K.M. Grant
Protozoan parasites, such as those responsible for malaria
and African Sleeping Sickness, represent a huge burden to
the developing world. Current chemotherapy to combat these
diseases is inadequate: antiquated, toxic and increasingly
ineffective due to drug resistance. In this article, the potential
usefulness of targeting key regulators of the parasite cell
cycle will be discussed, paying particular attention to three
families of protein kinases: Cyclin-dependent kinases, glycogen
synthase kinases and Aurora kinases. This review shall outline
their identification, which has been greatly accelerated by
the availability of parasite genome data, their validation
as bona fide regulators of the parasite cell cycle
and current data on the availability and anti-parasite activity
of inhibitors.
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Ultrastructural Alterations in Organelles of Parasitic
Protozoa Induced by Different Classes of Metabolic Inhibitors
J.C.F. Rodrigues and W. de Souza
Parasitic protozoa such as Leishmania, Trypanosoma,
Plasmodium, Toxoplasma gondii, Giardia and Trichomonas
are able to cause several diseases affecting millions of people
around the world with dramatic consequences to the socio-economic
life of the affected countries. Diseases like malaria, leishmaniasis
and trypanosomiasis have been classified by the World Health
Organization as neglected diseases, because they hasve been
almost completely forgotten by the governments as well as
the pharmaceutical companies. The specific chemotherapy currently
employed for the treatment of these diseases has serious limitations
due to lack of efficacy, toxic side effects, growth of drug-resistance
and high costs. Thus, it is urgent to develop new chemotherapeutic
agents that are more effective, safe and accessible. In this
context, several works have been focused on understanding
the effect of different drug-treatments on these parasitic
protozoa. Organelles and structures such as mitochondrion,
kinetoplast, apicoplast, glycosome, acidocalcisome, hydrogenosome,
plasma membrane and the cytoskeleton have been studied using
different approaches to identify new targets for the development
of new chemotherapeutic agents that are required. Some studies
on alterations in the fine structure, as assayed using electron
microscopy, have indicated the nature of lesions induced by
several drugs, allowing deductions on possible modes of action.
Here, we briefly review the available data of the effects
of several drugs on the ultrastructure of parasitic protozoa
and show how electron microscopy can contribute to elucidate
the different mechanisms of these anti-parasitic drugs.
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