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Infectious
Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Infectious Disorders
– Drug Targets
Volume 8, Number 1, March 2008
Contents
Preface: Infectious Disorders Drug Targets -
An Arsenal of Knowledge on Pathogen Targets Pp. 1
Babu L. Tekwani
[Abstract]
Genomic and Genetic Approaches for the Identification of Antifungal
Drug Targets Pp. 2-15
A. K. Agarwal, T. Xu, M. R. Jacob, Q. Feng, X. C. Li,
L. A. Walker and A. M. Clark
[Abstract]
Structural Analysis of Farnesyl Pyrophosphate
Synthase from Parasitic Protozoa, a Potential Chemotherapeutic
Target Pp. 16-30
Anuradha Srivastava, Prasenjit Mukherjee, Prashant V.
Desai, Mitchell A. Avery and Babu L. Tekwani
[Abstract]
The Use of Proteomics to Study Infectious Diseases
Pp. 31-45
E.O. List, D.E. Berryman, B. Bower, L. Sackmann-Sala,
E. Gosney,J. Ding, S. Okada and J.J. Kopchick
[Abstract]
Guest Editor: Editorial Pp. 46-47
Celestino Gonzalez
[Abstract]
Relationship Between Non-Genomic Actions of Estrogens
and Insulin Resistance Pp. 48-51
Ana Alonso and Celestino González
[Abstract]
Estrogen Regulation of Adipose Tissue Functions:
Involvement of Estrogen Receptor Isoforms
§
Pp. 52-60
V. Pallottini, P. Bulzomi, P. Galluzzo, C. Martini and
M. Marino
[Abstract]
Rapid Regulation of Pancreatic α-
and β-
Cell Signalling Systems by Estrogens Pp. 61-64
Cristina Ripoll, Ana B. Ropero, Paloma Alonso-Magdalena,
Ivan Quesada, Esther Fuentes and Angel Nadal
[Abstract]
Neuroprotective Effects of Estrogens: Cross-Talk
Between Estrogen and Intracellular Insulin Signalling
Pp. 65-67
Celestino González, Fernando Díaz and Ana
Alonso
[Abstract]
Abstracts
[Back to top]
Preface: Infectious Disorders Drug Targets -
An Arsenal of Knowledge on Pathogen Targets
Babu L. Tekwani
Most of the actions of estrogens are mediated by
two isoforms of the estrogen receptor (ER) encoded by different
genes, ERα
and ERβ,
which were cloned in 1986 and 1987, respectively. Both receptors
function as ligand-dependent transcription factors to regulate
gene expression according to the classical estrogen signalling
pathway. However, estrogen signalling seems to be more complicated
than the genomic pathway because several biological estrogen
actions are too fast to be compatible with a transcriptional
mechanism. Evidence has been accumulating indicating that
not all of the physiological actions of estrogen can be explained
according to a direct effect on gene transcription, and the
involvement of signalling pathways related to cytoplasmatic
proteins, growth factors and/or membrane-initiated responses
has been reported. This mode of action has been termed non-classical,
non-genomic or rapid effects of estradiol and it has been
related to an increase in NO release, calcium homeostasis,
cAMP accumulation or IGF pathway activation. However, the
molecular mechanisms responsible are poorly understood. In
this context, the existence of plasma membrane receptors has
been proposed to explain the rapid actions of estrogen.
What determines ERα
targeting to the plasma membrane? The main question is, what
is the role of these isoforms of ERα
in/on the plasma membrane? It has been proposed that post-translational
modifications of some ER proteins must occur to ensure targeting
to the membrane, including palmitoylation, which could be
related to facilitation of caveolin-1 binding, but more studies
are needed to answer this question.
Although the evidence suggests the existence of a close relationship
between estrogen and sensitivity to the action of insulin,
relatively few studies has attempted to solve the mystery
exists about the molecular basis of this relationship in insulin-dependent
tissues. Resolve these unknowns could have a major impact
on long-term therapy, and that resistance to the action of
insulin is the underlying cause of many diseases, for example,
the aging female as Type 2 diabetes, cardiovascular disease
circulatory, neurodegenerative diseases or some types of cancer.
Recent data have revealed a surprising role for estradiol
in regulating energy metabolism and opened new insights about
the regulation of the intracellular insulin signalling and
insulin secretion by ERα
and ERβ.
This new field of research promises radically to change our
knowledge about the mechanism of actions of the estrogens
and to contribute to understand better the therapeutic possibilities
of the estrogens receptor in order to improve some aspects
related to some menopause-relative diseases as insulin resistance,
ictus, cancer and so on.
The goal of these reviews is to highlight the important role
that the fast or non-genomic estrogen actions has at different
levels.
In this way, Dr. Ripoll et al. show in their review
that insulin release is controlled by estradiol due to the
existence of ERα
and ERβ
in plasma membrane of β-cells,
because 17β-estradiol
regulates KATP channel activity and glucose-induced [Ca2+]i
oscillations, eliciting changes in the activation of Ca2+-dependent
transcription factors.
Because an excess of white adipose tissue results in obesity
and estrogens promote, maintain, and control the typical distribution
of body fat and adipose tissue metabolism through still unknown
mechanisms, Dr. Pallottini et al. show in their review
the role of estrogens in adipose tissue differentiation and
in the protection against the onset of obesity, and in this
way they explain the underlying molecular mechanisms mediated
by estrogen receptor isoform ERα
and ERβ.
Dr. Alonso and Dr. González provide some evidences
that suggest the existence of a narrow interrelation between
the non-genomic action of estrogens and insulin sensitivity.
The resolution of the unknown questions about the molecular
mechanism of this interrelation would be able to have a great
long-term therapeutic repercussion in several associated pathologies
to the female aging, because insulin resistance could be the
underlying cause of some of them.
Finally, Dr. González et al. analyzed present
and future ways of the possible molecular mechanism involves
in the neuroprotective effect of estrogens on brain. The relationship
between insulin resistance states and neurodegenerative diseases
associated with aging in females, and the cross-talk between
estradiol and proteins includes in the IRS-1/PI3-k/Akt and
IGF-1-IR signalling pathways in brain, will lead to a more
complete understanding of the precise mechanism underlying
estradiol-mediated neuroprotection.
Dr. Celestino Gonzalez
Associated Professor of Physiology
DPTM. Functional Biology. Physiology Area
FAC. Medicine. Univ. Oviedo
C/Julian Claveria S/N 33006 Oviedo,
Spain
[Back to top]
Genomic and Genetic Approaches for the Identification of Antifungal
Drug Targets
A. K. Agarwal, T. Xu, M. R. Jacob, Q. Feng, X. C. Li,
L. A. Walker and A. M. Clark
Understanding how novel antifungal compounds work in
target cells is useful not only in facilitating the discovery
of new drugs but also new tools that can be used for further
exploration of the targeted biological pathways and their
regulation. Various genomic and genetic technologies have
been developed in the model yeast Saccharomyces cerevisiae,
and have been successfully used to identify drug target pathways.
This review discusses the methods developed for some of these
technologies, and how they have been used to evaluate the
cellular pathways affected by a variety of therapeutic drugs
and inhibitors. The advantages and disadvantages of each method
are considered, and new advances are highlighted where applicable.
The investigation of the mechanism of action of new antifungal
compounds will undoubtedly lead to the development of new
antifungal therapies targeting new fungal pathways that are
more specific and less toxic than currently available antifungal
drugs.
[Back to top]
Structural Analysis of Farnesyl Pyrophosphate Synthase from
Parasitic Protozoa, a Potential Chemotherapeutic Target
Anuradha Srivastava, Prasenjit Mukherjee, Prashant V.
Desai, Mitchell A. Avery and Babu L. Tekwani
Synthesis of farnesyl pyrophosphate (FPP), a key intermediate
of the isoprenoid biosynthesis pathway, is catalyzed by FPP
synthase (FPPS). Antiprotozoal properties of bisphosphonates,
which target FPPS, have generated interest in FPPS as a potential
antiprotozoal drug target. The genes encoding FPPS from parasitic
protozoa were assessed to analyze structural and functional
features of the enzyme. Comparisons of the FPPS from the parasitic
protozoa and search for conserved motifs revealed that FPPS
from both apicomplexan and trypanosomatid parasites show characteristic
conserved regions for example first aspartate rich motif (FARM)
contained within II conserved domain and the second aspartate
rich motif (SARM) contained within VI conserved domain. Phylogenetic
analysis of FPPS generated a tree with three distinct clusters.
Overall topology of the phylogenic tree constructed with small
subunit ribosomal RNA sequences was almost similar to that
constructed with FPPS sequences. Comparative homology modeling
and structural comparisons of FPPS from the parasitic protozoa
provided significant insights into common and distinct characteristics
of the enzyme. The critical interacting residues of the isopentenyl
pyrophosphate binding site are conserved across the enzymes
from the family except for malarial FPPS where the C-terminal
residues from the BXB motif of helix J were missing. Variations
noticed in aromatic residue pairs at the fourth and fifth
position upstream of the FARM, which play important role in
determination of chain length of the polyprenyl products,
may produce functional differences among protozoan FPPSs.
The structural comparison of protozoan FPPS may be useful
in designing common or selective FPPS inhibitors as potential
broad spectrum or selective antiprotozoal agents.
[Back to top]
The Use of Proteomics to Study Infectious Diseases
E.O. List, D.E. Berryman, B. Bower, L. Sackmann-Sala,
E. Gosney,J. Ding, S. Okada and J.J. Kopchick
Technology surrounding genomics, or the study of an organism’s
genome and its gene use, has advanced rapidly resulting in
an abundance of readily available genomic data. Although genomics
is extremely valuable, proteins are ultimately responsible
for controlling most aspects of cellular function. The field
of proteomics, or the study of the full array of proteins
produced by an organism, has become the premier arena for
the identification and characterization of proteins. Yet the
task of characterizing a proteomic profile is more complex,
in part because many unique proteins can be produced by the
same gene product and because proteins have more diverse chemical
structures making sequencing and identification more difficult.
Proteomic profiles of a particular organism, tissue or cell
are influenced by a variety of environmental stimuli, including
those brought on by infectious disease. The intent of this
review is to highlight applications of proteomics used in
the study of pathogenesis, etiology and pathology of infectious
disorders. While many infectious agents have been the target
of proteomic studies, this review will focus on those infectious
diseases which rank among the highest in worldwide mortalities,
such as HIV/AIDS, tuberculosis, malaria, measles, and hepatitis.
[Back to top]
Editorial: Infectious Disorders Drug Targets
- An Arsenal of Knowledge on Pathogen Targets
Infectious disorders have always received special attention
due to their global importance in human health. Recently this
area has been in special focus due to increased global biological
threats, bioterrorism and prominent media coverage given to
some recent infectious disease epidemics [1, 2]. Global climate
changes have also led to an increased risk of infectious diseases
[3]. Reemergence of the infectious diseases and continuous
emergence of drug resistance strains of the pathogens underscores
the need for identification of new agents; indeed, the building
and continuous augmentation of an “armamentarium of
multiple drugs” is necessary to cope up with the problem
of further development of resistance [4]. The conventional
approaches to drug discovery, particularly the technologies
of in vitro individual target-based and pathogen
culture-based screening, may not be sufficient to sustain
this level of innovation and drug discovery/development. Additionally,
morbidity and mortality attributable to tropical diseases,
particularly the parasitic infections including malaria, leishmaniasis
and trypanosomiasis (new and old world) are staggering. Together
they are a tremendous burden in morbidity, mortality, and
economic hardship. More than half of the world’s population
is currently at risk of infection with one or the other tropical
disease pathogens. In addition, it has been estimated that
almost one third of world’s population has been exposed
to tuberculosis. Therefore TB and tropical infections collectively
are a major global health predicament. Despite of this, tropical
parasitic diseases and TB have been largely ignored in relation
to advances in modern drug discovery. Infectious Disorders
Drug Targets (IDDT) shall continue with the mission to provide
a high impact platform for discussions on new discoveries,
recent developments and critical evaluation of the knowledge
on novel drug & vaccine targets of infectious disease
pathogens as well as recent technological advancements in
this important area related to global health.
The technological advancements and accumulation of wealth
of information on infectious disease pathogens have resulted
into an augmented interest and exponential rise in the knowledge
regarding distinct biochemical, molecular and functional characteristics
of potential target enzyme as well as metabolic pathways of
the pathogens [5-9]. A few selected examples of these advancements
are sequencing of pathogen genomes; whole pathogen genome
expression analysis, target and pathways analysis through
DNA/protein microarrays & global expression profiling
of the pathogen genomes; high throughput structural and functional
genomics; molecular targets-based high throughput screening
approaches; generation of large compound libraries directed
to special molecular-targets; fragmented screening of privileged
chemical libraries; live cell bio-imaging technologies; renewed
interests and application of high impact technologies in natural
products as important source of novel pharmacophores. These
developments have resulted into a paradigm shift in approach
of new drug discovery against the infectious disorders. The
pathogen genome data, functional genomics and system biology
approaches have helped in construction/reconstruction of almost
complete metabolic maps of the pathogens [10]. This information
has been useful in identification of metabolic pathways, enzymes,
receptors, cellular function, which are unique to the pathogens
[11]. Such knowledge can be directly applied to molecular-targets
based drug-design.
The process of new drug discovery is a mammoth task which
requires gigantic investments, and in light of the low level
of profitability associated with the treatments for tropical
parasitic diseases, discovery efforts have not been sufficiently
systematic, rigorous and comprehensive. Although the incidences
of parasitic infections are mostly centered in tropical regions,
the impacts, especially economic, of the disease are global.
Emergence of few Private-Public Partnerships (PPPs), for example
Medicines for Malaria Venture (MMV); Drugs for Neglected Diseases
Initiatives (DNDi); Global Funds to fight AIDS, Tuberculosis
and Malaria; and interests of governmental and non-profit
agencies has greatly stimulated the research for discovery
and development of new drugs against the neglected infectious
diseases [12].
Continuing with the legacy of predecessors future missions
of IDDT would be targeted to present critical analysis of
common target enzymes/metabolic pathways of the infectious
disease pathogens, compilation of up-to-date information on
molecular approaches for controlling emerging infectious diseases,
SARS and other related viral pathogens, skin infectious diseases,
Prion diseases, neglected eukaryotic infectious pathogens
e.g., parasitic helminthes, Apicomplexan parasites and trypanosomatids.
An special IDDT issue dedicated to in silico approaches
in study of pathogen targets, including the comparative structural
analysis of potential common target enzymes shall be applied
to new drug discovery research. The comparative phylogenetic
and structure analysis of farenesyl pyrophosphate synthase,
an enzyme involved in synthesis of a key isoprenoid intermediate,
presented by Srivastava et al. [13] in this issue
presents a case of structural and functional genomics approach
for design and discovery of antiprotozoal drugs with broad
spectrum activity against multiple species of parasitic protozoa.
List et al. [14] present a comprehensive account
and analysis of the reports related to application of proteomics
for investigation of pathogenesis and molecular targets of
infectious disease pathogens. The yeast, Saccharomyces
cerevisiae, has been extensively investigated at cellular,
molecular and genetic levels. The S. cerevisiae has
been used as genetic and genomic tool to investigate new antifungal
drug targets. Agarwal et al. [15] have analyzed the
application of these tools for investigating mode of action
of new as well as currently used antifungal drugs and also
identification new drug targets. The critical reviews directed
to in depth discussions and current status of the knowledge
regarding individual molecular targets and molecular basis
of pathogenesis of a specific group of infectious disorder,
for example stress regulation by the host during infectious
diseases, shall help in formulating future strategies of research
in these areas.
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[3] Senior, K. Lancet Infect. Dis., 2008,
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[4] Fournier, P.E.; Drancourt, M.; Raoult, D. Lancet Infect.
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[5] Chen, T. Infect. Disord. Drug Targets, 2006,
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[6] Mishra, K.P.; Ganju, L.; Sairam, M.; Benerjee, P.K.; Sawney,
R.C. Biomed. Pharmacother., 2008, 62,
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[7] Koehn, F.E. Prog. Drug Res., 2008,
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[8] Manjasetty , B.A.; Turnbull, A.P., Panjikar, S.; Bussow,
K.; Chance, M.R. Proteomics, 2008, 8,
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[9] Murillo A.C.; Li, H.Y.; Alber, T.; Baker, E.N.; Berger,
J.M.; Cherney, L.T.; Cherney, M.M.; Cho, Y.S.; Eisenberg,
D.; Garen, C.R.; Goulding C.W.; Hung L.W.; Ioerger, T.R.;
Jacobs, W.R.; James, M.N.; Kim, C.; Krieger, I.; Lotts. J.S.;
Sankarnarayanan, R.; Segelke, B.W.; Terwilliger, T.C.; Waang,
F.; Wang, S.; Sacchettni, J.C. Infect. Disorder Drug Targets,
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[10] Pinney, J.W.; Papp, B.; Hyland, C.; Wambu L, Westhead,
D.R.; McConkey. G.A. Trends Parasitol., 2007,
23, 548.
[11] Sakata, T.; Winzeler, E.A. Molec. Biosyst., 2008,
3, 841.
[12] Molyneux, D. Control of Human Parasitic Diseases,
2006 Academic Press, London.
[13] Srivastava, A.; Mukherjee, P.; Desai, P.; Avery, M.A.;
Tekwani B.L. Infect. Disorders Drug Targets, 2008.
[14] List, E.O. Berryman, D.E.; Bower, B., Sackmann-Sala;
Gosney, E.; Ding, J.; Okada, S.; Kopchick, J.J. Infect.
Disorders Drug Targets, 2008.
[15] Agarwal A.; Xu, T.; Jacob, M.R.; Feng, Q.; Li, X.C.;
Walker, L.A.; Clarks A.M. Infect. Disorders Drug Targets,
2008.
Babu L. Tekwani
Editor-in-Chief
National Center for Natural Products Research
School of Pharmacy, University of Mississippi
University MS 38677,
USA
E-mail- btekwani@olemiss.edu
[Back to top]
Relationship Between Non-Genomic Actions of Estrogens and
Insulin Resistance
Ana Alonso and Celestino González
Numerous experimental and clinical data show that the
physiological actions of insulin and sexual steroids interact
in target tissues for these hormones. In the other hand, sexual
steroids has effects on peripheral tissues, and since the
skeletal muscle is the main responsible for peripheral glucose
uptake, it would be possible that the sexual steroids induce
directly in the muscle a decrease of the sensibility of this
tissue to insulin action. Some of the biological actions of
the estrogens are too fast like to be compatible with this
classical mechanism of action, and this mechanism has been
called not classical, non-genomic or rapid actions of the
estrogens. Moreover, some experiments have shown that low
concentrations of estradiol, induce an increase in the rate
of IRS-1 phosphorylation, promotes the association between
IRS-1 and the subunit of PI3-k, p85α,
causes a decrease in the rate of IRS-1 serine phosphorylation
and increases the rate of Akt phosphorylation. Therefore,
the evidences suggest the existence of a narrow interrelation
between the estrogens and insulin sensitivity, but relatively
few studies have tried to resolve the molecular base of this
relation in insulin-dependent tissues. The resolution of these
unknown questions would be able to have a great long-term
therapeutic repercussion. In this sense, we should not forget
that insulin resistance is the underlying cause of several
associated pathologies to the female aging, as Type 2 diabetes,
cardio-circulatory pathology or neurodegenerative disease.
[Back to top]
Estrogen Regulation of Adipose Tissue Functions: Involvement
of Estrogen Receptor Isoforms§
V. Pallottini, P. Bulzomi, P. Galluzzo, C. Martini and
M. Marino
Adipose tissue has recently been described as one of
the major endocrine gland that plays a role in energy homeostasis,
lipid metabolism, immune response, and reproduction. An excess
of white adipose tissue, caused by a complex interaction between
genetic, hormonal, behavioral, and environmental factors,
results in obesity: a heterogeneous disorder that predisposes
humans to a variety of diseases. Among several hormones, estrogens
promote, maintain, and control the typical distribution of
body fat and adipose tissue metabolism through still unknown
mechanisms. These steroids are known to regulate fat mass,
adipose deposition and differentiation, and adipocyte metabolism.
Moreover, estrogen deficiency results in increases in adipose
tissue, preferentially in visceral fat, which would link obesity
to the susceptibility of related disorders.
In this review the role of estrogens in adipose tissue differentiation
and in the protection against the onset of obesity will be
discussed with particular attention being drawn to the underlying
molecular mechanisms mediated by estrogen receptor isoforms
ERα
and ERβ.
[Back to top]
Rapid Regulation of Pancreatic α-
and β-
Cell Signalling Systems by Estrogens
Cristina Ripoll, Ana B. Ropero, Paloma Alonso-Magdalena,
Ivan Quesada, Esther Fuentes and Angel Nadal
Rapid estrogen actions are triggered after estrogens
are bound to a variety of proteins in organelles other than
the nucleus. Those include classic estrogen receptors ERα
and ERβ,
novel membrane proteins that behave as estrogen receptors
such as GPR30, ion channels, and other ligand receptors.
In pancreatic α
and β-cells,
estrogens binding to a non-classical membrane estrogen receptors
at physiological concentrations regulate ion channels and
[Ca2+]i
signals, provoking important physiological responses. In β
-cells, 17
β-estradiol regulates KATP
channel activity and glucose-induced [Ca2+]i
oscillations, eliciting changes in insulin release and the
activation of Ca2+ -dependent
transcription factors. In α
-cells, 17 β-estradiol
abolishes low glucose-induced [Ca2+]i
oscillations.
[Back to top]
Neuroprotective Effects of Estrogens: Cross-Talk Between Estrogen
and Intracellular Insulin Signalling
Celestino González, Fernando Díaz and Ana
Alonso
The incidence of neurodegenerative diseases is higher
in postmenopausal women that young women. In this sense, Alzheimer’s
and Parkinson’s diseases, ischemic brain injury and
memory or cognitive dysfunction increase dramatically when
the ovarian function declines. On the other hand, insulin
resistance represents an independent factor in the etiology
of age-associated coronary and cerebrovascular disease. Therefore,
depression, neurodegenerative diseases such as Alzheimer’s
and Parkinson’s diseases and memory or cognitive dysfunction
should be considered, in some cases, a result of metabolic
syndrome, and that postmenopausal women are more vulnerable
that young women to these diseases
Several studies have suggested that the molecular mechanism
by which estradiol exerts its neuroprotective effects involves
activation of the PI3-k signalling pathway, which is activated
by insulin and IGF-1. Therefore, it seems possible that ERα
can interact with these signalling pathways, mainly with PI3-k
and IRS-1, to promote neuroprotective effects in the brain.
In particular, IGF-I seems to be particularly important in
the process of neuroprotection; it can reverse age-related
effects and attenuate the age-related decrease in cerebral
glucose utilization. Moreover, gonadal hormones have been
found to regulate IGF-I receptor. Therefore, it seems clear
that the interaction of both systems plays a role in the prevention
of neuronal age-related effects. These findings suggest that
by interacting with some components of the IGF-I signalling
pathway, ERα
affects the actions of IGF-I in the brain and suggest future
avenues of research.
The relationship between insulin resistance states associated
with aging in females, and the cross-talk between estradiol
and proteins includes in the IRS-1/PI3-k/Akt and IGF-1-IR
signalling pathways, will lead to a more complete understanding
of the precise mechanism underlying estradiol-mediated neuroprotection.
Numerous clinical studies have demonstrated that the incidence
of neurodegenerative diseases in higher in postmenopausal
women that young women. In this sense, Alzheimer’s and
Parkinson’s disease, ischemic brain injury and memory
or cognitive dysfunction increase dramatically when the ovarian
function declines. Moreover, estrogen replacement therapy
seems to be a good element in order to decrease the risk and/or
severity of neurodegenerative conditions, and it would be
able to improve some aspects related to memory and learning
process.
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