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Infectious Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Infectious Disorders
– Drug Targets
Volume 7, Number 3, September 2007
Contents
Zn Finger Containing Proteins as Targets for
the Control of Viral Infections Pp. 204-212
C. C. García and E. B. Damonte
[Abstract]
Targeting Iron Acquisition by Mycobacterium tuberculosis
Pp. 213-220
Ryan R. Monfeli and Craig Beeson
[Abstract]
Targeted Anti-Bacterial Therapy Pp. 221-229
Iftach Yacoby and Itai Benhar
[Abstract]
Strategic Paradigm Shifts in the Antimicrobial Drug
Discovery Process of the 21st
Century Pp. 230-237
Luis E. N. Quadri
[Abstract]
HIV-1 Capsid Protein and Cyclophilin A as New Targets
for Anti AIDS Therapeutic Agents Pp. 238-244
Jiebo Li, Shixing Tang, Indira Hewlett and Ming Yang
[Abstract]
In Search of Drug Targets for Mycobacterium tuberculosis
Pp. 245-250
Hemant J. Purohit, Simrita Cheema, Sadhana Lal, Chandrakant
P. Raut and Vipin C. Kalia
[Abstract]
Interaction and Assembly of HBV Structural Proteins:
Novel Target Sites of Anti-HBV Agents Pp. 251-256
In-Geol Choi and Yeon Gyu Yu
[Abstract]
Phenothiazines as Anti-Multi-Drug Resistant Tubercular
Agents Pp. 257-265
L. Amaral, M. Martins and M. Viveiros
[Abstract]
Drug Targets from Human Pathogenic Amoebas: Entamoeba
histolytica, Acanthamoeba polyphaga and Naegleria fowleri
Pp. 266-280
R. N. Ondarza
[Abstract]
Abstracts
[Back to top]
Zn Finger Containing Proteins as Targets for
the Control of Viral Infections
C. C. García and E. B. Damonte
The zinc finger proteins have fascinated many research groups
because of their modular assembly, broad range of biological
functions and more recently because they are attractive targets
for antiviral therapy. The zinc finger domain is a very stable
structural element whose hallmark is the coordination of a
zinc ion by several amino acid residues, usually cysteines
and histidines. These structural motifs are associated with
protein-nucleic acid recognition as well as protein-protein
interactions. The biological function of the zinc finger proteins
is strongly dependent on the zinc ion, which assure integrity
and stability. Thus, the disruption of critical zinc finger
viral proteins represents a fundamentally new approach to
inhibit viral replication in the absence of mutations leading
to drug resistance phenotypes. This review summarizes the
drug design and potential therapeutic applications of viral
zinc fingers disrupting agents for the control of viral diseases.
[Back to top]
Targeting Iron Acquisition by Mycobacterium tuberculosis
Ryan R. Monfeli and Craig Beeson
Tuberculosis (TB) caused by the pathogen Mycobacterium
tuberculosis continues to be a major worldwide health
problem. Lack of compliance to the complex, multi-drug therapy
regimen has resulted in multidrug-resistant TB and a need
for new drug targets. Siderophore molecules used for iron
acquisition are good targets because pathogen survival and
virulence is directly related to iron availability. Indeed,
a key host defense mechanism is the production of siderocalins
that sequester iron-laden siderophores and M. tuberculosis
replicates poorly in the absence of these siderophores. A
number of investigators have recently targeted siderophores
or their synthesis for the development of novel anti-tubercular
therapeutics. For example, one group has synthesized ‘dominant
negative’ mycobactin siderophore analogues that significantly
inhibit bacterial growth. Several other groups have developed
agents that directly inhibit enzymes involved in siderophore
synthesis. A profoundly different approach is to target the
iron dependent regulator protein (IdeR) that represses siderophore
synthesis genes and virulence factors when sustainable iron
levels have been achieved. Loss of the repression leads to
iron overload and oxidative damage. In contrast, enhanced
IdeR repression at low iron levels attenuates M. tuberculosis
virulence in mice. The structural basis for iron activation
and IdeR binding to DNA has been recently reported and these
insights have enabled the structure-based design of agents
that target IdeR function. Small peptides that either enhance
IdeR repression or inhibit IdeR dimerization demonstrate that
IdeR activity can be rationally modulated.
[Back to top]
Targeted Anti-Bacterial Therapy
Iftach Yacoby and Itai Benhar
The increasing development of bacterial resistance to traditional
antibiotics has reached alarming levels, thus necessitating
a strong need to develop new antimicrobial agents. These new
antimicrobials should possess novel modes of action and/or
different cellular targets compared with the existing antibiotics.
As a result, new classes of compounds designed to avoid defined
resistance mechanisms are undergoing pre clinical and clinical
evaluation. Microbial and phage genomic sequencing are now
being used to find previously unidentified genes and their
corresponding proteins. In both traditional and newly developed
antibiotics, the target selectivity lies in the drug itself,
in its ability to affect a mechanism that is unique to prokaryotes.
As a result, a vast number of potent agents that, due to low
selectivity, in addition to the pathogen also affect the eukaryote
host have been excluded from use as therapeutics. Such compounds
could be re-considered for clinical use if applied as part
of a targeted delivery platform where the drug selectivity
is replaced by target-selectivity borne by the targeting moiety.
With a large number of antibodies and antibody-drug conjugates
already approved or near approval as cancer therapeutics,
targeted therapy is becoming increasingly attractive and additional
potential targeting moieties that are non-antibody based,
such as peptides, non-antibody ligand-binding proteins and
even carbohydrates are receiving increasing attention. Still,
targeted therapy is mostly focused on cancer, with targeted
anti bacterial therapies being suggested only very recently.
This review will focus in the various methods of antimicrobial
targeting, by systemic and local application of targeted antimicrobial
substances.
[Back to top]
Strategic Paradigm Shifts in the Antimicrobial Drug
Discovery Process of the 21st
Century
Luis E. N. Quadri
The numbers of global infections produced by bacterial strains
that are resistant to single and multiple antimicrobial drugs
are on the rise. Concomitant with this alarming upward trend,
there is a clear downward trend in the intent and determination
of pharmaceutical companies to develop novel antimicrobials.
One of the pressing goals to confront the twenty first century’s
public health challenges brought about by the escalating antibacterial
drug resistance problem is the development of an armamentarium
of new chemotherapeutic agents. Two interconnected strategic
paradigm shifts in the drug discovery process that are anticipated
to facilitate the achievement of this goal are discussed herein.
One is an antimicrobial to anti-infective (ATA) paradigm shift.
The other is a shift from a target candidate prioritization
(TCP) paradigm that is dominated by an essential target preference
criterion to an alternative paradigm that relies on a less
restrictive criterion, one that does not exclude conditionally
essential targets. Examples of conditionally essential targets
for the development of anti infectives include the enzymes
involved in the biosynthesis of small molecule virulence effectors
such as non ribosomal peptide polyketide derived iron scavenging
siderophores. Siderophores are utilized for iron uptake by
many pathogenic bacteria, including Mycobacterium
and Yersinia species. The recent progress towards
developing inhibitors of siderophore biosynthesis is discussed
herein.
[Back to top]
HIV-1 Capsid Protein and Cyclophilin A as New Targets
for Anti AIDS Therapeutic Agents
Jiebo Li, Shixing Tang, Indira Hewlett and Ming Yang
The emergence of drug resistant mutations in current anti-HIV-1
drug regimens is an important determinant of the eventual
drug failure. New drug development strategies that focus on
either new targets or novel compounds are therefore critical
for future effective viral suppression in HIV-1 infected individuals.
Particularly, virus assembly and disassembly are attractive
candidate processes for antiviral intervention. HIV-1 capsid
(CA) protein and human cyclophilin A (CypA) play important
roles in these processes, which consequently make them attractive
targets of high priority. Inhibitors that target CA or CypA
have been mainly divided into three classes: (1) compounds
that specifically block capsid protein formation; (2) compounds
that directly bind to the capsid and inhibit its assembly;
and (3) compounds that bind to Cyp A and possibly inhibit
the disassembly of capsid conical cores. Here, we give an
overview of HIV-1 CA protein and Cyp A as new targets for
potential anti-AIDS therapeutic agents.
[Back to top]
In Search of Drug Targets for Mycobacterium tuberculosis
Hemant J. Purohit, Simrita Cheema, Sadhana Lal, Chandrakant
P. Raut and Vipin C. Kalia
Mycobacterium tuberculosis is the etiological agent
for tuberculosis in humans. The studies related to survival
of this pathogen in the human host and development of drugs
against reveal that the organism uses a complex physiology
to adapt to the host environment. Many studies were targeted
to key enzymes that allow this pathogen to either survive
or remain latent within the host. Most of the models, which
address the survival of pathogen, have evaluated limited dissolved
oxygen and prevailing stress conditions. Hence, the truncated
citric acid cycle, with the glyoxylate shunt was suggested
as an option for survival of the pathogen and pathogenesis.
We propose that the precursors to support this pathway could
also be generated via enzymatic conversion involving poly-β-hydroxybutyrate
(PHB). We have used available genome sequence data and analyzed
for the possible enzymatic conversions that can generate glyoxylate,
acetyl CoA, and other enolases that can also be useful for
various fatty acid transformations. The enzymes for accumulation
and further hydrolysis of PHB were examined in sequence data
analysis. The target enzymes were searched for in the genome
using identified conserved domains. Using M. tuberculosis
H37Rv as a model bacterium a supportive pathway has been envisaged
and integrated with glyoxylate cycle to provide a complete
option to pathogen for sustainable consumption of available
carbon source(s). The study proposes that the enzymes of PHB
synthesis and hydrolysis are possible targets for drug design,
and that this should be considered when evaluating isocitrate
lyase and malate synthase as targets.
[Back to top]
Interaction and Assembly of HBV Structural Proteins:
Novel Target Sites of Anti-HBV Agents
In-Geol Choi and Yeon Gyu Yu
Human hepatitis B virus (HBV) causes chronic hepatitis disease
which is a major public health problem worldwide. HBV has
4 genes encoding viral DNA polymerase, protein X and two structural
proteins, the surface and core proteins. HBV DNA polymerase
has been a primary target for the development of anti-HBV
agents due to its enzymatic nature, and several nucleoside
derivatives that inhibit HBV polymerase are currently used
as anti-HBV therapeutics. On the other hand, accumulating
information on the capsid assembly and the maturation process
of HBV particles provides additional approaches for the development
of anti-HBV agents. Proper interaction between core proteins
is required for assembly of the nucleocapsid, and the specificity
of the interactions between the capsid and surface proteins
is essential for the maturation of active HBV in infected
cells. In this article, the assembly process of active HBV
particles and approaches to utilize the interactions of HBV
structural proteins as target site for the development of
anti-HBV agents are reviewed. In particular, novel approaches
to target the assembly process and the interaction between
HBV structural proteins are introduced.
[Back to top]
Phenothiazines as Anti-Multi-Drug Resistant Tubercular
Agents
L. Amaral, M. Martins and M. Viveiros
Pulmonary tuberculosis (TB) has again become a global problem:
it infects 2.2 billion people world-wide, caused the deaths
of over 3 million last year and will produce over 8 million
new cases of TB this coming year. Although effective therapy
is widely available for antibiotic susceptible strains of
Mycobacterium tuberculosis, current drugs are relatively
useless against multi-drug resistant infections (MDRTB). Mortality
is almost complete within two years regardless of therapy,
and in the case of co-infection with HIV/AIDS, mortality is
100% within a few months of diagnosis especially the M.
tuberculosis strain in XDRTB. As of the time of this
writing no new effective anti-TB drugs have been made available
by the pharmaceutical industry and XDRTB. Because TB is an
intracellular infection of the non-killing macrophage of the
lung, any agent that is to prove effective must have activity
against MDRTB and XDRTB strains that have been phagocytosed
by the human macrophage. This review intents to provide cogent
in vitro, ex vivo and in vivo evidence
that supports the use of a variety of commonly available phenothiazines
for the therapy of MDRTB and XDRTB, especially when the prognosis
of the infection is poor and the use of the recommend agents
can take place along lines of “compassionate therapy”.
In addition, we will describe the macrophage assay as indispensable
when an agent is to be further studied for its effectiveness
as an anti-TB drug. In vitro studies if not complemented
by ex vivo studies will for the most part be dead-ended
since few agents that have activity in vitro have
any activity against phagocytosed M. tuberculosis.
[Back to top]
Drug Targets from Human Pathogenic Amoebas: Entamoeba
histolytica, Acanthamoeba polyphaga and Naegleria fowleri
R. N. Ondarza
In this review we present our search for the presence of drug
targets in several species of human pathogenic parasites,
mainly the amoebas Entamoeba histolytica, Acanthamoeba
polyphaga and Naegleria fowleri. We started
with an analysis of the concepts of essentiality and validity
of the targets and continue with a description of the main
characteristics of pathogenicity of these amoebas. We then
proceed to evaluate these targets arranged mainly in seven
groups corresponding to: a) enzymes which are secreted by
these parasites to invade the human host, for example proteinases,
phospholipases and pore forming peptides, b) glycolytic enzymes
from Entamoeba and Naegleria, like the PPi-dependent
phospho-fructokinase that differ from the host enzyme, c)
thiols and enzymes of redox metabolism, present only in trypanosomatids,
Entamoeba and Naegleria, such as the trypanothione/trypanothione
reductase that maintains the reducing environment within the
cell, d) antioxidant enzymes to regulate the oxidative stress
produced by the phagocytic cells of the host or by the parasite
metabolism, like the trypanothione peroxidase in connection
with the NADPH-dependent trypanothione/trypanothione reductase
which maybe is present in Naegleria fowleri, and
peroxiredoxin in E. histolytica, e) enzymes for the
synthesis of trypanothione like the ornithine decarboxylase,
spermidine synthase and trypanothione synthetase, f) some
of the proteins that assemble the secretory vesicles with
the cell membrane, like the synaptobrevins and finally, g)
encystment pathways and cyst-wall assembly proteins. Some
of the above new targets will need to be studied in a more
detail, including crystallographic studies of the enzymes
for rational drug design. As far as we know there are no advanced
crystallographic studies being conducted on targets from these
three amoebas, as has been the case for various targets from
the trypanosomatids.
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