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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 21, 2009
Contents
Therapeutic Potential of Peptide Motifs –
Part II
Executive Editor: Jean-Claude Hervé
Editorial: Pp. 2375-2376
The Roles of Antimicrobial Peptides in Innate Host
Defense Pp. 2377-2392
G. Diamond, N. Beckloff, A. Weinberg and
K.O. Kisich
[Abstract]
Multifunctional Antimicrobial Proteins
and Peptides: Natural Activators of Immune Systems Pp.
2393-2413
F. Niyonsaba, I. Nagaoka, H. Ogawa and
K. Okumura
[Abstract]
Peptides Targeting Angiogenesis Related
Growth Factor Receptors Pp. 2414-2429
L.D. D’Andrea, A.D. Gatto, L. De Rosa,
A. Romanelli and C. Pedone
[Abstract]
Naturally Occurring and Synthetic Peptides
Acting on Nicotinic Acetylcholine Receptors Pp.
2430-2452
I.E. Kasheverov, Y.N. Utkin and
V.I. Tsetlin
[Abstract]
Current Status and Perspectives in Peptide
Receptor Radiation Therapy Pp. 2453-2462
C. Ansquer, F. Kraeber-Bodéré
and J.F. Chatal
[Abstract]
Peptide Inhibitors Targeting Protein
Kinases Pp. 2463-2470
H. Eldar-Finkelman and M. Eisenstein
[Abstract]
Peptides as Signaling Inhibitors for
Mammalian MAP Kinase Cascades Pp. 2471-2480
M. Gaestel and M. Kracht
[Abstract]
Targeting Rho GTPases by Peptidic Structures
Pp. 2481-2487
F. Marchioni and Y. Zheng
[Abstract]
Modulating Proteostasis: Peptidomimetic
Inhibitors and Activators of Protein Folding Pp.
2488-2507
F. Hatahet and L.W. Ruddock
[Abstract]
Therapeutic Potential of Peptide Motifs
Against HIV-1 Reverse Transcriptase and Integrase Pp.
2508-2519
M.L. Andréola
[Abstract]
Cyclin Dependent Kinases as Attractive
Targets to Prevent Transcription from Viral Genomes Pp.
2520-2532
F. Kashanchi and K. Kehn-Hall
[Abstract]
Abstracts
[Back to top]
Editorial: Therapeutic Potential of Peptide Motifs
– Part II
The production of new molecular entities endowed
with salutary medicinal properties is a formidable challenge;
synthetic molecules that can bind with high sequence specificity
to a chosen target in a protein or gene sequence are of major
interest in medicinal and biotechnological contexts. The general
awareness of the importance of peptides in physiology and
pathophysiology has markedly increased over the last few years.
With progresses in the analysis of whole genomes, the knowledge
base in gene sequence and expression data useful for protein
and peptide analysis has drastically increased. The medical
need for relevant biomarkers is enormous. This is particularly
true for the many types of cancers, but also for other diseases,
e.g. type 2 diabetes or cardiac diseases, which
also lack adequate diagnostic markers with high specificity
and sensitivity. Imaging technologies for early detection
of diseases, proteomic and peptidomic multiplex techniques
have markedly evolved in recent years. Peptides can indeed
be regarded as ideal agents (as "magic bullets")
for diagnostic and therapeutic applications because of their
fast clearance, rapid tissue penetration, and low antigenicity,
and also of their easy production, allowing innumerable biological
applications. They can easily be engineered to improve their
biological activities as well as their stability and their
efficient delivery to specific targets. This second themed
issue of Current Pharmaceutical Design, for which I have the
honour to be Executive Guest Editor, addresses topical issues
to some of these potential utilizations of peptide motifs
for a variety of genetic and acquired diseases.
A collection of biological processes protect both animal and
plant kingdoms from pathogens and tumour cells, detecting
a wide variety of agents (from viruses to parasitic worms),
distinguishing them from the organism's own healthy cells
and tissues. The protective immunity against pathogenic infection
can be divided into innate and adaptive immunities, respectively
representing the first defence barrier in the host and the
second line defence including T (cellular) and B (humoral)
cell mediated responses. Antimicrobial peptides (AMPs) are
an essential part of innate immunity that evolved in living
organisms over 2.6 billion years to combat microbial challenge,
and their fundamental biological role in vivo has
been proposed to be the elimination of pathogenic microorganisms,
including Gram-positive and -negative bacteria, fungi, and
viruses. Gill Diamond, Nicholas Beckloff, Aaron Weinberg and
Kevin O. Kisich [1] summarise AMP structure and function and
overview the varied activities of AMPs in mammals, which may
help to understand their roles in innate host defence. AMPs
found in the skin, beside their endogenous antibiotic ability,
play important roles in normal skin function and in various
skin conditions, overviewed by François Niyonsaba,
Isao Nagaoka, Hideoki Ogawa and Ko Okumura [2], who also explore
the future of AMPs as potential therapeutics for various infection-
and/or inflammatory-related skin diseases.
Growth factors (GFs), extracellular signalling polypeptides
capable of stimulating cellular growth, proliferation and
cellular differentiation, exert a wide spectrum of biological
activities selectively binding to and activating specific
membrane receptors which then transfer the message to cell
interior, inducing specific biochemical pathways. GFs are
especially involved in the regulation of angiogenesis, a physiological
process of remodelling of the vascular tissue, characterized
by the branching out of a new blood vessel from a pre-existing
vessel, underlining several pathologies. Molecules interfering
with the molecular recognition between a GF and its receptor,
and able to modulate angiogenesis, have a big pharmacologic
interest. Luca D. D’Andrea, Annarita Del Gatto, Lucia
De Rosa, Alessandra Romanelli and Carlo Pedone [3] show how
peptides are useful tools to develop new lead compounds disrupting
protein-protein interface for pharmacological applications.
Nicotinic acetylcholine receptors (nAChRs) are a large family
of ligand gated ion channels that mediate signal transduction
at the post-synaptic membrane of cholinergic synapses, such
as the neuromuscular junction. Agonist binding by nAChR induces
conformational changes triggering the opening of the transmembrane
channel. Competitive antagonists of different chemical nature,
including peptides, can interact with the agonist binding
sites and prevent receptor activation. nAChRs also embody
several other binding sites which can bind polypeptide compounds.
Peptide binding to these sites does not necessarily block
receptor, however it can modulate its function. Igor E. Kasheverov,
Yuri N. Utkin and Victor I. Tsetlin [4] explain how application
of peptides for receptor studies has allowed revealing many
details of their function, allowing the development of new
drugs targeting nAChRs against different human diseases and
as a means against nicotine addiction.
The fact that regulatory peptide receptors are frequently
overexpressed in different human cancers allowed to exploit
the specific receptor binding properties of peptides by their
labelling with a radionuclide and their use as carriers to
guide the radioactivity to the tissues expressing their specific
receptors. Catherine Ansquer, Françoise Kraeber-Bodéré
and Jean François Chatal [5] present the current state
of clinical use of these "intelligent drug molecules"
for diagnosis and therapy of neuroendocrine tumours and discuss
potential directions for optimization and future developments,
as the optimization of peptide analogues or derivatives, increasing
the access and binding to specific receptors on the tumour
sites, enhancing radiotoxicity profile and multimodality strategies.
Protein kinases are essential regulators of most (if not all)
biological processes, and their abnormal activity has been
implicated as causal factors in many human diseases, including
cancer, diabetes or neurodegenerative disorders. So protein
kinases represent attractive targets for drug design and compounds
that manipulate their cellular activity are of enormous therapeutic
potential. Inhibition of protein kinase activity may be achieved
either by blocking the phosphorylation activity or by disrupting
protein-protein interactions. Peptides that can mimic most
truly these regulatory modes are favourite choice for protein
kinase-targeting. Hagit Eldar-Finkelman and Miriam Eisenstein
[6] focus on the strategies to design such peptide inhibitors,
targeting in particular the serine/threonine protein kinase
family. Among protein kinases, mitogen-activated protein kinase
(MAPK) cascades are key signalling pathways involved in the
regulation of normal cell proliferation, survival and differentiation.
Evidences that aberrant MAPK activation in cancers promotes
cell proliferation, cell survival and metastasis support current
efforts to identify approaches to inhibit this pathway. Matthias
Gaestel and Michael Kracht [7] present an overview of the
different strategies to specifically inhibit or modulate MAPK
signaling by peptides interfering with autoinhibition and
docking of protein kinases.
Ras-homologous (Rho) GTPases play key roles in the regulation
of numerous cellular functions associated with malignant transformation
and metastasis. Localized at membranes, Rho GTPases become
activated upon stimulation of cell surface receptors. In their
GTP-bound (=active) state, they bind to effector proteins,
thereby triggering specific cellular responses. Members of
this family are pivotal regulators of actin reorganization,
cell motility, cell-cell and cell-extracellular matrix adhesion
as well as of cell cycle progression, gene expression and
apoptosis. Filippo Marchioni and Yi Zheng [8] summarize the
recent advances in the design and application of a number
of polypeptide and peptidomimetic structures that specifically
target individual members of Rho GTPases and their up- or
down-stream signaling regulators/effectors with an emphasis
on cancer, inflammation and neurodegenerative diseases.
Protein folding is the physical process by which a polypeptide
folds into its characteristic and functional three-dimensional
structure. It is a careful balance between productive folding
and misfolding leading to aggregation and/or degradation of
misfolded and partially folded intermediates. Protein folding
being governed by intra- and inter-molecular protein interactions,
it is ideally suited to targeting by peptidomimetic drugs
that mirror those interactions, but there are serious issues
to contend with, in particular relating to specificity. Feras
Hatahet and Lloyd W. Ruddock [9] present the different approaches
that can be used to alter proteostasis with an emphasis on
peptidomimetic inhibitors and activators of protein folding.
They examine the available modulators, their mechanisms of
action and potential limitations, including the problems of
specificity in altering proteostasis.
The replicative cycle of human immunodeficiency virus (HIV-1),
the causal agent of AIDS, is intensively studied to identify
targets leading to the design of specific inhibitors. Current
treatments consist in the combination of drugs targeting reverse
transcriptase and protease but, despite the multiple clinical
benefits of this combination therapy, the emergence of resistance
highlights the need for new anti-HIV agents. Agents able to
interfere with additional steps of viral replication, such
as integration of viral DNA in the host genome, would improve
the antiviral potency of the treatment. Marie-Line Andréola
[10] shows that disruption of protein-protein interactions
in retroviral enzymes may constitute an alternative way to
achieve HIV-1 inhibition. Cyclin-dependent kinases (CDK) belong
to a group of protein kinases originally discovered as being
involved in the regulation of the cell cycle, but in fact
play roles in a vast number of cellular functions, including
cell cycle regulation, transcription, neuronal differentiation
and splicing. CDK deregulation is prevalent in both cancer
and viral infection and, in strategies developed for drug-resistant
HIV strains for example, cellular proteins, particularly CDKs,
are now emerging as potential targets for new antiretroviral
therapies. Fatah Kashanchi and Kylene Kehn-Hall [11] outline
the various functions of CDKs, their role in the life cycle
of selected retroviruses and herpesviruses, and the pharmacological
CDK inhibitors that have been focused on in terms of viral
inhibition.
I wish to thank all the authors and co-authors for their commitments
and the anonymous reviewers who contributed by their constructive
remarks to the excellence of this issue.
References
[1] Diamond G, Beckloff N, Weinberg A, Kisich KO. The Roles
of Antimicrobial Peptides in Innate Host Defense. Curr Pharm
Des 2009; 15(21): 2377-2392.
[2] Niyonsaba F, Nagaoka I, Ogawa H, Okumura K. Multifunctional
antimicrobial proteins and peptides: Natural activators of
immune systems. Curr Pharm Des 2009; 15(21): 2393-2413.
[3] D’Andrea LD, Gatto AD, Rosa LD, Romanelli A, Pedone
C. Peptides targeting angiogenesis related growth factor receptors.
Curr Pharm Des 2009; 15(21): 2414-2429.
[4] Kasheverov IE, Utkin YN, Tsetlin VI. Naturally Occurring
and Synthetic Peptides Acting on Nicotinic Acetylcholine Receptors.
Curr Pharm Des 2009; 15(21): 2430-2452.
[5] Ansquer C, Kraeber-Bodéré F, Chatal JF.
Current status and perspectives in peptide receptor radiation
therapy. Curr Pharm Des 2009; 15(21): 2453-2462.
[6] Eldar-Finkelman H. Eisenstein M. Peptide Inhibitors Targeting
Protein Kinases. Curr Pharm Des 2009; 15(21): 2463-2470.
[7] Gaestel M, Kracht M. Peptides as signaling inhibitors
for mammalian MAPK kinase cascades. Curr Pharm Des 2009; 15(21):
2471-2480.
[8] Marchioni F, Zheng Y. Targeting Rho GTPases by peptidic
structures. Curr Pharm Des 2009; 15(21): 2481-2487.
[9] Hatahet F. Ruddock LW. Modulating proteostasis: Peptidomimetic
inhibitors and activators of protein folding. Curr Pharm Des
2009; 15(21): 2488-2507.
[10] Andréola ML. Therapeutic potential of peptide
motifs against HIV-1 reverse transcriptase and integrase.
Curr Pharm Des 2009; 15(21): 2508-2519.
[11] Kashanchi F, Kehn-Hall K. Cyclin Dependent Kinases as
attractive targets to prevent transcription from viral genomes.
Curr Pharm Des 2009; 15(21): 2520-2532.
Jean-Claude Hervé
Institut de Physiologie et Biologie Cellulaires
UMR CNRS 6187, PBS, 40 avenue du R. Pineau
86022 POITIERS Cédex,
France
E-mail: Jean.Claude.Herve@univ-poitiers.fr
[Back to top]
The Roles of Antimicrobial Peptides in Innate Host Defense
G. Diamond, N. Beckloff, A. Weinberg and K.O. Kisich
Antimicrobial peptides (AMPs) are multi-functional peptides
whose fundamental biological role in vivo has been
proposed to be the elimination of pathogenic microorganisms,
including Gram-positive and -negative bacteria, fungi, and
viruses. Genes encoding these peptides are expressed in a
variety of cells in the host, including circulating phagocytic
cells and mucosal epithelial cells, demonstrating a wide range
of utility in the innate immune system. Expression of these
genes is tightly regulated; they are induced by pathogens
and cytokines as part of the host defense response, and they
can be suppressed by bacterial virulence factors and environmental
factors which can lead to increased susceptibility to infection.
New research has also cast light on alternative functionalities,
including immunomodulatory activities, which are related to
their unique structural characteristics. These peptides represent
not only an important component of innate host defense against
microbial colonization and a link between innate and adaptive
immunity, but also form a foundation for the development of
new therapeutic agents.
[Back to top]
Multifunctional Antimicrobial
Proteins and Peptides: Natural Activators of Immune Systems
F. Niyonsaba, I. Nagaoka, H. Ogawa and K. Okumura
In addition to the physical barrier of the stratum corneum,
cutaneous innate immunity also includes the release of various
humoral mediators, such as cytokines and chemokines, recruitment
and activation of phagocytes, and the production of antimicrobial
proteins/peptides (AMPs). AMPs form an innate epithelial chemical
shield, which provides a front-line component in innate immunity
to inhibit microbial invasion; however, this might be an oversimplification
of the diverse functions of these molecules. In fact, apart
from exhibiting a broad spectrum of microbicidal properties,
it is increasingly evident that AMPs display additional activities
that are related to the stimulation and modulation of the
cutaneous immune system. These diverse functions include chemoattraction
and activation of immune and/or inflammatory cells, the production
and release of cytokines and chemokines, acceleration of angiogenesis,
promotion of wound healing, neutralization of harmful microbial
products, and bridging of both innate and adaptive immunity.
Thus, better understanding of the functions of AMPs in skin
and identification of their signaling mechanisms may offer
new strategies for the development of potential therapeutics
for the treatment of infection- and/or inflammation-related
skin diseases. Here, we briefly outline the structure, regulation
of expression, and multifunctional roles of principal skin-derived
AMPs.
[Back to top]
Peptides Targeting Angiogenesis
Related Growth Factor Receptors
L.D. D’Andrea, A.D. Gatto, L. De Rosa, A. Romanelli
and C. Pedone
Growth factors (GFs) are extracellular signaling polypeptides
regulating cell proliferation, differentiation and survival.
They exert a wide spectrum of biological activities selectively
binding to and activating specific membrane receptors which
then transfer the message to cell interior inducing specific
biochemical pathways. GFs are especially involved in the regulation
of angiogenesis, a physiological process underlining several
pathologies. Molecules able to modulate angiogenesis, interfering
with the molecular recognition between a GF and its receptor,
have a big pharmacologic interest. Either GF and the receptor
are potential drug target. Peptides are useful molecules to
develop new lead compounds disrupting protein-protein interface
for pharmacological applications. In this review we describe
peptides targeting the receptors of the pro-angiogenic growth
factors FGF, PDGF and VEGF. The biological function and the
structure of each growth factor/receptor system are discussed,
as well as the molecular interaction between peptides and
the receptors. Finally, we highlight the pharmacological and
diagnostic applications of these peptides in angiogenesis
related diseases.
[Back to top]
Naturally Occurring and Synthetic
Peptides Acting on Nicotinic Acetylcholine Receptors
I.E. Kasheverov, Y.N. Utkin and V.I. Tsetlin
Nicotinic acetylcholine receptors (nAChRs) are pentameric
membrane-bound proteins belonging to the large family of ligand-gated
ion channels. nAChRs possess various binding sites which interact
with compounds of different chemical nature, including peptides.
Historically first peptides found to act on nAChR were synthetic
fragments of snake α-neurotoxins,
competitive receptor antagonists. Later it was shown that
fragments of glycoprotein from rabies virus, having homology
to α-neurotoxins,
and polypeptide neurotoxins waglerins from the venom of Wagler’s
pit viperTrimeresurus (Tropidolaemus) wagleri bind
in a similar way, waglerins being efficient blockers of muscle-type
nAChRs. Neuropeptide substance P appears to interact with
the channel moiety of nAChR. β-Amyloid,
a peptide forming senile plaques in Alzheimer’s disease,
also can bind to nAChR, although the mode of binding is still
unclear. However, the most well-studied peptides interacting
with the ligand-binding sites of nAChRs are so-called α-conotoxins,
peptide neurotoxins from marine snails of Conus genus.
First α-conotoxins
were discovered in the late 1970s, and now it is a rapidly
growing family due to isolation of peptides from multiple
Conus species, as well as to cloning, and chemical
synthesis of new analogues. Because of their unique selectivity
towards distinct nAChR subtypes, α-conotoxins
became valuable tools in nAChR research. Recent X-ray structures
of α-conotoxin
complexes with acetylcholine-binding protein, a model of nAChR
ligand-binding domains, revealed the details of the nAChR
ligand-binding sites and provided the basis for design of
novel ligands.
[Back to top]
Current Status and Perspectives
in Peptide Receptor Radiation Therapy
C. Ansquer, F. Kraeber-Bodéré and
J.F. Chatal
Regulatory peptide receptors are overexpressed in numerous
human cancers. The specific receptor binding property of peptides
can be exploited by their labelling with a radionuclide and
their use as carriers to guide the radioactivity to the tissues
expressing their specific receptors. During the past decade,
radiolabelled receptor-binding peptides have emerged as an
important class of radiopharmaceuticals for tumour diagnosis
and therapy. The first and most successful imaging agents
to date are somatostatin analogues which are routinely used
for somatostatin receptor scintigraphy. Peptide receptor radionuclide
therapy (PRRT) with 90Y-DOTA-octreotide
and 177Lu-DOTA-octreotate
in neuroendocrine tumours (NETs) results in symptomatic improvement,
prolonged survival, and enhanced quality of life. The results
in terms of tumour regression are very encouraging with few
and mostly mild side effects when patients are carefully
selected and kidney protective agents are given. Nevertheless
much profit can be gained from improving the available receptor-targeting
strategies and developing new strategies. In this review,
the current state of clinical use of radiolabelled peptides
for diagnosis and therapy of NETs is presented. In addition,
potential directions for optimization and future developments
are discussed. These include the optimization of peptide analogues
or derivatives, increasing the access and binding on specific
receptors on the tumour sites, increasing radiotoxicity
profile and multimodality strategies. Other peptides such
as minigastrin, glucagon-like peptide-1 (GLP-1), cholecysto-
kinin (CCK), bombesin (BN)/gastrin-releasing peptide (GRP),
substance P, neurotensin (NT), neuropeptide Y (NPY) and RGD
peptides are promising for PRRT and currently under preclinical
and clinical development.
[Back to top]
Peptide Inhibitors Targeting Protein
Kinases
H. Eldar-Finkelman and M. Eisenstein
Phosphorylation by protein kinases is a central theme
in biological systems. Aberrant protein kinase activity has
been implicated in a variety of human diseases, therefore,
modulation of kinase activity represents an attractive therapeutic
approach for the treatment of human illnesses. Development
and design of specific inhibitors for protein kinases thus
became a major strategy in many drug discovery programs. Inhibition
of protein kinase activity may be achieved by blocking the
phosphorylation activity or by disrupting protein-protein
interactions. Peptides that can mimic most truly these regulatory
modes are favorite choice for protein kinase-targeting. Here
we focus on important motifs regulating the protein kinase
signaling network and described how they may be exploited
for peptide drug design.
Protein kinases are important regulators of most, if not all,
biological processes. Their abnormal activity has been implicated
as causal factors in many human diseases, including cancer,
diabetes and neurodegenerative disorders [1-3]. Protein kinases
are thus attractive targets for drug design and compounds
that manipulate their cellular activity are of enormous therapeutic
potential. With a target in hand, medicinal chemists can generate
low molecular weight compounds that bind the target with high
affinity and alter its biological behavior. In many cases,
however, drugs fail as they lack appropriate pharmaceutical
properties and are of limited specificity resulting in unfavorable
side effects. Under these circumstances, the use of peptides,
which copy 'natural' motifs that specifically influence kinase
activity and/or its intracellular interactions with cognate
partners, may be a promising approach for selective inhibition
of protein kinases. In this review we focus on the strategies
to design such peptide inhibitors, focusing mainly on the
serine/threonine protein kinase family.
[Back to top]
Peptides as Signaling Inhibitors
for Mammalian MAP Kinase Cascades
M. Gaestel and M. Kracht
Mammalian MAPK cascades are essential for cellular signaling
in response to mitogenic signals and stress-stimuli to regulate
proliferation, differentiation and apoptosis. The three major
MAPK cascades, ERK1/2-, JNK- and p38, maintain signaling specificity
by scaffolding proteins and by specific docking interactions
between pathway components. The structures mediating these
interactions include the domain of versatile docking (DVD)
responsible for MAP3K-MAP2K-interaction and the common docking
(CD)-domain and the ED (glutamate/aspartate)-site of MAPKs
together with the various docking (D) motifs in MAP2Ks, MAPK
substrates and MAPK-phosphatases. Several of these interactions
have been studied in great detail. First approaches to use
this knowledge to develop peptides that specifically inhibit
MAPK signaling in disease models have been reported. It becomes
obvious that specificity of peptides competing with kinase-docking
is comparable to or even superior to small molecule ATP-competitive
inhibitors. In addition to specifically targeting protein-protein
interactions, the ultimate efficacy of these peptide inhibitors
in vivo also depends on their delivery, stability and toxicity
in living cells and in the whole organism.
[Back to top]
Targeting Rho GTPases by Peptidic Structures
F. Marchioni and Y. Zheng
Rho GTPases represent a family of small GTP-binding proteins
that are involved in many important cellular functions relevant
to cancer including cell cytoskeleton organization, migration,
transcription, and proliferation. Since deregulation of members
of Rho GTPase family is often found associated with many disease
states, targeting of Rho GTPases and related signaling pathways
for potential therapeutic benefits has been extensively pursued.
Recent progress in this field of studies by peptide and peptidomemic
inhibitors has provided important validations to this principle.
The possibility to design and synthesize specific peptides
that can bind to specific surface of the targeting proteins
to elicit transient and specific blockade of the signal flows
that require defined protein-protein interactions makes peptide
inhibitors an attractive approach. In this review we summarize
the recent advances in the design and application of a number
of polypeptide and peptidomimetic structures that specifically
target individual members of Rho GTPases and their up- or
down-stream signaling regulators/effectors with an emphasis
on cancer, inflammation and neurodegenerative diseases. The
principle derived from the peptidic inhibitors has led to
discoveries of the first generation of small molecule inhibitors
of Rac GTPase of the Rho family. The implication of these
studies in the pathobiology of various human diseases makes
targeting Rho GTPases a valid strategy for future therapies.
[Back to top]
Modulating Proteostasis: Peptidomimetic
Inhibitors and Activators of Protein Folding
F. Hatahet and L.W. Ruddock
Protein folding in the cell is a complex process with
a fine balance between productive and non-productive folding.
To modulate, either up-regulating or down-regulating, the
level of one specific protein with multiple approaches is
possible, including the modulation of catalysed protein folding,
the use of chemical and pharmacological chaperones, alteration
of natural protein-protein interactions, the regulation of
degradative pathways and manipulation of natural control mechanisms,
such as the heat shock response and the unfolded protein response.
Errors in proteostasis are linked to a wide range of disease
states and many examples exist of the successful manipulation
of proteostasis for the partial or complete elimination of
the disease phenotype, including for many amyloid based diseases
such as Parkinson’s and Alzheimer’s as well as
for ‘loss-of-function’ diseases such as Fabry’s
and Gaucher’s diseases. This review takes an overview
of the different approaches that can be used to alter proteostasis
with an emphasis on peptidomimetic inhibitors and activators
of protein folding. It covers the modulators available, their
mechanisms of action and potential limitations, including
the problems of specificity in altering proteostasis.
[Back to top]
Therapeutic Potential of Peptide
Motifs Against HIV-1 Reverse Transcriptase and Integrase
M.L. Andréola
Multiple clinical benefits have been obtained thanks
to the combination of drugs targeting several steps of the
HIV-1 replication. However, despite such combination therapy,
complete eradication of the virus cannot be attained. Moreover,
emergence of resistance observed under treatment and the lengthening
life expectancy of treated patients highlight the need for
new anti-HIV agents. Peptide-based compounds that exhibit
anti RT and anti integrase activities were particularly described.
Active peptides have been obtained from several ongoing approaches.
The study of interaction between viral proteins inside the
preintegration complex, and the growing knowledge of interactions
between viral proteins and cellular partners, have generated
a useful source of data for the development of peptide inhibitors.
Recent data were also obtained from the observation that viral
enzymes such as RT and integrase are fully active when they
are in a dimeric (RT) or oligomeric state. Peptides derived
from the interface of dimers are also of interest. The obtention
of efficient small molecules as competitive oligomerization
inhibitors is problematic, but anyway, improved cellular uptake
and chemical modifications that were obtained in the past
ten years allowed numerous peptide drugs to reach the clinic.
Finally, a new promising class of peptide inhibitors is emerging
called “shiftides”, which interfere with the ability
of IN to adopt an oligomeric active state.
[Back to top]
Cyclin Dependent Kinases as Attractive
Targets to Prevent Transcription from Viral Genomes
F. Kashanchi and K. Kehn-Hall
Most viral treatments target the virus itself, providing
very specific effects and limiting side-effects on uninfected
cells. However, this strategy of drug design often results
in resistant viruses, especially among RNA viruses. Therefore,
the focus has turned to drugs that target cellular proteins
that are essential for viral replication, but not for cellular
viability. Pharmacological CDK inhibitors are a prime example
of this type of approach. Reviewed within are the various
functions of CDKs, their role in the life cycle of selected
Retroviruses and Herpesviruses, and the pharmacological CDK
inhibitors that have been focused on in terms of viral inhibition.
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