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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 24, 2008
Contents
Therapeutic Potential of Peptide Motifs - Part I
Executive Editor: Jean-Claude Hervé
Editorial: Pp. 2383-2384
Radiometal Targeted Tumor Diagnosis and Therapy with
Peptide Hormones Pp. 2385-2400
D. Zwanziger and A.G. Beck-Sickinger
[Abstract]
Radiolabelled Peptides and Monoclonal
Antibodies for Therapy Decision Making in Inflammatory Diseases
Pp. 2401-2414
G. Malviya, A. Signore, B. Laganà
and R. A. Dierckx
[Abstract]
Cell Penetrating Peptides for In
Vivo Molecular Imaging Applications Pp.
2415-2427
V. Kersemans, K. Kersemans and
B. Cornelissen
[Abstract]
Peptide Microarrays: Next Generation
Biochips for Detection, Diagnostics and High-Throughput Screening
Pp. 2428-2438
M. Uttamchandani and S.Q. Yao
[Abstract]
Peptide Nucleic Acids (PNAs) as Diagnostic
Devices for Genetic and Cytogenetic Analysis Pp.
2439-2444
F. Pellestor, P. Paulasova and S. Hamamah
[Abstract]
Candidate Circulating Biomarkers for
the Cardiovascular Disease Continuum Pp. 2445-2461
O. Dotsenko, J. Chackathayil, J.V. Patel, P.S.
Gill and G.Y.H. Lip
[Abstract]
Conus Venoms - A Rich Source
of Peptide-Based Therapeutics Pp. 2462-2479
T.S. Han, R.W. Teichert, B.M. Olivera and
G. Bulaj
[Abstract]
Peptides Targeting Voltage-Gated Calcium Channels
Pp. 2480-2491
R.S. Norton and S.I. McDonough
[Abstract]
Animal Peptides Targeting Voltage-Activated
Sodium Channels Pp. 2492-2502
B. Billen, F. Bosmans and J. Tytgat
[Abstract]
Animal Toxins Acting on Voltage-Gated
Potassium Channels Pp. 2503-2518
S. Mouhat, N. Andreotti, B. Jouirou and
J-M. Sabatier
[Abstract]
Abstracts
[Back to top]
Editorial: “Therapeutic Potential of
Peptide Motifs” - Part I
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 not only for 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. The present issue
of Current Pharmaceutical Design, for which I have the honour
to be Executive Guest Editor, addresses topical issues to
some of these potential utilisations of peptide motifs for
a variety of genetic and acquired diseases.
During the past years, proofs of the fact that peptide receptors
can be successfully used for in vivo targeting of
human cancers, have been provided. The molecular basis for
targeting grounds on the in vitro observation is
that peptide receptors can be expressed in large quantities
in certain tumours. The clinical impact is at the diagnostic
level: in vivo receptor scintigraphy uses radiolabelled
peptides for the localisation of tumours and of their metastases.
Peptidic tumour targeting agents can be sub-divided into the
following segments: peptide, spacer, bifunctional chelator,
and radioisotope. Denise Zwanziger and Annette G. Beck-Sickinger
[1] summarise the biological and chemical properties of peptide
hormones and their prerequisites for use as tumour targeting
agents for both diagnostic and therapeutic purposes, alone
or in combination with other peptide hormones or as the carriers
for cytotoxic agents.
Radiolabelled peptides have emerged as an important class
of radiopharmaceuticals for imaging and therapy of inflammatory
diseases and malignancies. These radiopharmaceuticals, which
bind with high affinity and specificity to their receptors
present in these structures, have an excellent diagnostic
potential for the imaging of patients with chronic inflammatory
diseases or tumours. The challenge is to label bioactive peptides
without affecting their receptor binding properties. Size,
plasma protein binding, lipophilicity and sensitivity to proteolysis
are to be considered, with biodistribution, metabolism and
excretion characteristics. G. Malviya, A. Signore, B. Laganà
and R.A. Dierckx [2] describe the characteristics of peptides,
cytokines and monoclonal antibodies with a particular emphasis
to their role for therapy decision making and follow up in
different inflammatory diseases.
Cell penetrating peptides (CPPs) have the promising ability
to cross the plasma membranes of mammalian cells in an apparently
energy- and receptor-independent fashion. Most of the currently
recognised CPPs are of cationic nature and derived from viral,
insect or mammalian proteins endowed with membrane translocation
properties. The exact mechanism underlying this translocation
remains poorly understood, but this ability is being exploited
to deliver a broad range of problematic therapeutic cargos,
such as proteins, DNA oligomers, antibodies, peptide-nucleic
acids, imaging agents, magnetic nanoparticles and liposomes
in a variety of situations and biological systems. Veerle
Kersemans, Ken Kersemans and Bart Cornelissen [3] present
an overview of the use of CPPs for molecular imaging and discussed
the difficulties and pitfalls of their utilisation.
Peptide microarray technologies, based on the high-density
immobilisation of surface-bound peptides on the solid planar
supports, allowing them to sense protein activity (like substrates)
or to act as small molecule ligands (for potential therapeutic
leads) in profiling, detection or diagnostic applications.
Peptides can be rapidly synthesised as large, defined library
sets, which can be installed with orthogonal or directed chemical
tags for convenient immobilisation on arrays. These approaches,
allowing to miniaturise, parallelise and automate high throughput
screening, have emerged as one of the most prominent and revolutionary
technologies currently available for multiplexed detection.
Mahesh Uttamchandani and Shao Q. Yao [4] chart the progress
made in peptide microarrays, with a focus on the recent advances
that could impact how the field will be shaped in the coming
years.
Peptide nucleic acids (PNAs) are synthetic homologs of nucleic
acids, in which the phosphate-sugar polynucleotide backbone
is replaced by repeating N-(2-aminoethyl) glycine units linked
by amine bonds and to which the nucleobases are fixed. This
structure gives PNAs the capacity to hybridise with high affinity
and specificity to complementary sequences of DNA and RNA,
and also confers remarkable resistance to DNAses and proteinases.
Originally conceived as ligands for the study of double stranded
DNA, the unique physico-chemical properties of PNAs have led
to the development of a large variety of research and diagnostic
assays, including antigene and antisense therapy, genome mapping
and mutation detection. F. Pellestor, P. Paulasova and S.
Hamamah [5], overview PNAs properties and highlight the techniques
exploiting PNA technology in molecular genetics and cytogenetics.
Cardiovascular disease is a significant cause of morbidity
and mortality, making cardiovascular prevention an important
public health goal. The use of cardiac biomarkers of myocardial
injury, inflammation, and haemodynamic stability represents
a potential, noninvasive method to identify asymptomatic individuals,
who are most likely to develop cardiovascular disease. Several
known biomarkers predict cardiovascular risk above and beyond
the conventional risk factors, useful in establishing the
diagnosis, gauging prognosis, and evaluating the response
to therapy. O. Dotsenko, J. Chackathayil, J.V. Patel, P.S.
Gill and G.Y.H. Lip [6] outline the main principles of biomarker
qualification entered into clinical practice, overview the
development of targeted biomarkers across the cardiovascular
“continuum” and discuss the evidence from epidemiological
and clinical studies, advocating the potential clinical use
of the most promising plasma biomarkers (particularly C-reactive
protein, coagulation and inflammatory mediators and natriuretic
peptides).
Predatory cone snails (genus Conus) produce a rich array of
venoms that collectively contain an estimated 100,000 small,
disulfide-rich peptides, termed conotoxins or conopeptides.
Over the last few decades, the conopeptides have revealed
a remarkable diversity of pharma-cological function and utility,
and conopeptides studied in animal models have exhibited antinociceptive,
antiepileptic, neuroprotective or cardio protective activities.
Screening results also suggest applications of conotoxins
in cancer, neuromuscular and psychiatric disorders. Additional
potentially important applications of conotoxin research are
the discovery and validation of new therapeutic targets, also
defining novel binding sites on the already validated molecular
targets. T.S. Han, R.W. Teichert1, B.M. Olivera and G. Bulaj
[7] summarise recent efforts in the discovery of conopeptides,
and their preclinical and clinical development.
Calcium ions, because of their chemical properties and their
very high free concentration gradient between the extra and
intra-cellular media (about four orders of magnitude), are
of central importance in cellular physiology. The rapid entry
of calcium into cells through the activation of voltage-gated
calcium channels, directly affects membrane potential and
contributes to electrical excitability, repetitive firing
patterns, excitation-contraction coupling, gene expression,
etc. Many peptides are potent and highly selective blockers
or modulators of calcium channel function, and are as such
valuable pharmacological tools and potentially valuable, leads
for the development of human therapeutics. Raymond S. Norton
and Stefan I. McDonough [8] discuss aspects of the pharmacology
and physiology of peptide toxins and how the natural toxins
might be mimicked by non-peptide (peptidomimetic) compounds
that potentially have more favourable properties as therapeutic
agents.
Sodium channels underlie propagated electrical signalling
in most excitable cells, including neurons and the myocytes
of skeletal and cardiac muscles. These proteins are targeted
by various current therapeutic drugs to fight such illnesses
as pain, myotonias, epilepsies, cardiac arrhythmias, etc.
Typically, these problems are indeed associated with the overactivity
of sodium channels leading to hyperexcitability in the relevant
tissue. Several isoforms of voltage-activated sodium channels
are specifically targeted by various venom peptides. Bert
Billen, Frank Bosmans and Jan Tytgat [9] present the mechanisms
of action of animal venom peptides that target voltage-activated
sodium channels and address their potential therapeutical
applications.
Voltage-gated potassium (Kv) channels are the major determinants
of cellular repolarisation in excitable cells (they open in
response to depolarization and facilitate selective K+
efflux across the plasma membrane). On account of the importance
of exquisitely timed cellular repolarisation in controlling
action potential morphology and duration, Kv channels are
attractive therapeutic targets, particularly for drugs aimed
at controlling aberrant electrical excitability (observed
in cardiac arrhythmia or epilepsy for example). Toxins selective
for Kv channels are widely represented in animal venoms. S.
Mouhat, N. Andreotti, B. Jouirou and J.M Sabatier [10] show
how the ability of structurally divergent toxins to interact
with a particular Kv channel relies onto a similar spatial
distribution of amino acid residues and overview the therapeutic
value of the Kv channel blockers in the potential treatment
of different human diseases, as autoimmune disorders, inflammatory
neuropathies or cancer.
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] Zwanziger D, Beck-Sickinger AG. Radiometal Targeted Tumor
Diagnosis and Therapy with Peptide Hormones. Curr Pharm Des
2008; 14(24): 2385-2400.
[2] Malviya G, Signore A, Laganà B, Dierckx RA. Radiolabelled
peptides and monoclonal antibodies for therapy decision making
in inflammatory diseases. Curr Pharm Des 2008; 14(24): 2401-2414.
[3] Kersemans V, Kersemans K, Cornelissen B. Cell penetrating
peptides for in vivo molecular imaging applications.
Curr Pharm Des 2008; 14(24): 2415-2427.
[4] Uttamchandani M, Yao SQ. Peptide Microarrays: Next Generation
Biochips for Detection, Diagnostics and High-Throughput Screening.
Curr Pharm Des 2008; 14(24): 2428-2438.
[5] Pellestor F, Paulasova P, Hamamah S. Peptide Nucleic Acids
(PNAs) as diagnostic devices for genetic and cytogenetic analysis.
Curr Pharm Des 2008; 14(24): 2439-2444.
[6] Dotsenko O, Chackathayil J, Patel JV, Gill PS, Lip GYH.
Candidate circulating biomarkers for the cardiovascular disease
continuum. Curr Pharm Des 2008; 14(24): 2445-2461.
[7] Han TS, Teichert RW, Olivera BM, Bulaj G. Conus Venoms
- A Rich Source of Peptide-Based Therapeutics. Curr Pharm
Des 2008; 14(24): 2462-2479.
[8] Norton RS, McDonough SI. Peptides targeting voltage-gated
calcium channels. Curr Pharm Des 2008; 14(24): 2480-2491.
[9] Billen B, Bosmans F, Tytgat J. Animal peptides targeting
voltage-activated sodium channels. Curr Pharm Des 2008; 14(24):
2492-2502.
[10] Mouhat S, Andreotti N, Jouirou B, Sabatier JM. Animal
toxins acting on voltage-gated potassium channels. Curr Pharm
Des 2008; 14(24): 2503-2518.
Jean-Claude Hervé
Interactions et Communications Cellulaires
UMR CNRS 6187, PBS, 40 avenue du R. Pineau
86022 POITIERS Cédex
France
[Back to top]
Radiometal Targeted Tumor Diagnosis and Therapy with Peptide
Hormones
D. Zwanziger and A.G. Beck-Sickinger
Radiometal labeled peptide hormones are promising tools for
a new generation of radiopharmaceuticals, because their receptors
frequently are overexpressed in many human tumors. Furthermore,
peptide hormones are characterized by different advantages
for clinical application, such as high tumor-to-background
ratios as well as rapid blood clearance. Peptidic tumor targeting
agents can be sub-divided into the following segments: peptide,
spacer, bifunctional chelator and radioisotope.
Here the biological and chemical properties of peptide hormones
are summarized as well as their prerequisites for their use
as tumor targeting agents. Additionally, promising bifunctional
chelators and radioisotopes for radiometal labeling are reviewed.
Some few special peptide hormones that have been pre-clinically
or clinically investigated are furthermore presented, such
as somatostatin, bombesin (BBS) / gastrin releasing peptide
(GRP), vasoactive intestinal peptide (VIP) and neuropeptide
Y (NPY).
In vitro and in vivo investigations of the
binding affinity, selectivity, metabolic stability, bioavailability
and biodistribution of radio-labeled peptide hormones could
lead to potential peptide-based tumor targeting agents for
tumor diagnosis and therapy.
[Back to top]
Radiolabelled Peptides and Monoclonal Antibodies for Therapy
Decision Making in Inflammatory Diseases
G. Malviya, A. Signore, B. Laganà
and R. A. Dierckx
Radiolabelled peptides and monoclonal antibodies are an emerging
class of radiopharmaceuticals for imaging inflammation with
clinical implications for several chronic inflammatory disorders
for diagnosis, therapy decision making and follow up. In the
last decades, a number of novel monoclonal antibodies and
peptides have been introduced for the treatment of different
inflammatory disorders and also labelled with a variety of
radionuclides depending upon the specific applications, diagnostic
or therapeutic, by using direct or indirect methods. These
radiopharmaceuticals bind to their targets with high affinity
and specificity and therefore have an excellent diagnostic
potential for the imaging of patients with chronic inflammatory
diseases. In this review article we describe the characteristics
of peptides, cytokines and monoclonal antibodies with a particular
emphasis on their role in therapy decision making and follow
up in different inflammatory diseases.
[Back to top]
Cell Penetrating Peptides for In Vivo Molecular Imaging
Applications
V. Kersemans, K. Kersemans and
B. Cornelissen
Cell penetrating peptides (CPPs) are a relatively new class
of peptides that have the promising capability to cross cell
membranes. While details remain to be resolved, various non-receptor-mediated
endocytic pathways likely contribute most to the cell penetrating
properties of these peptides. CPPs have been used to deliver
many different cargos – ranging from radionuclides and
other peptides to antibodies and nanoparticles – into
cells. Besides many different drug delivery applications,
CPPs have also seen a limited use in molecular imaging. Molecular
imaging of intracellular and intranuclear targets, by techniques
such as SPECT, PET, optical imaging, and MRI, relies heavily
on the delivery of contrast agents to the cytoplasm and/or
nuclei of the target tissue. Therefore, the number of applications
in molecular imaging of intracellular targets has remained
relatively low, because of the effective barrier presented
by the cell membrane. One of the key strategies to overcome
this challenge is the introduction of membrane-transducing
peptides in the design of new contrast agents. This review
presents an overview of the literature on CPPs, focusing on
their use for molecular imaging. Applications using proteins
and peptides, DNA/RNA, and CPP-loaded cells as the imaging
agents will be looked at. Moreover, the difficulties and pitfalls
regarding the use of CPPs in molecular imaging will be discussed.
[Back to top]
Peptide Microarrays: Next Generation Biochips for Detection,
Diagnostics and High-Throughput Screening
M. Uttamchandani and S.Q. Yao
Peptide microarrays have become increasingly accessible in
recent years and as a result, more widely applied. Beyond
its initial utility in substrate profiling, researchers are
adopting peptide microarrays for the comparative screening
of many different classes of enzymes, proteins/ proteomes
and even living cells. Understanding the basis of peptide
interactions at these diverse levels provides an unprecedented
window into dissecting the complex cellular circuitries and
molecular architectures of living systems. The peptides on
the arrays may serve to sense protein activity (like substrates)
or act as small molecule ligands (for potential therapeutic
leads) in profiling, detection or diagnostic applications.
This review will chart the progress made in peptide microarrays,
with a focus on the recent advances that could impact how
the field will be shaped in the coming years. These developments,
along with the diminishing costs of library synthesis and
growing commercial support, recognize that peptide microarrays
will no longer remain just a vital research tool, but also
a platform that could now be harnessed for wider drug discovery
and point-of-care applications.
[Back to top]
Peptide Nucleic Acids (PNAs) as Diagnostic Devices for Genetic
and Cytogenetic Analysis
F. Pellestor, P. Paulasova and S. Hamamah
The peptide nucleic acids (PNAs) constitute a remarkable new
class of synthetic nucleic acids analogs, based on peptide-like
backbone. This structure gives to PNAs the capacity to hybridize
with high affinity and specificity to complementary RNA and
DNA sequences, and a great resistance to nucleases and proteinases.
Originally conceived as ligands for the study of double stranded
DNA, the unique physico-chemical properties of PNAs have led
to the development of a large variety of research and diagnostic
assays in the field of genetics, including genome mapping
and mutation detection. Over the last few years, the use of
PNAs has also proven its powerful usefulness in cytogenetics
for the rapid in situ identification of human chromosomes
and the detection of aneuploidies. Recent studies have reported
the successful use of chromosome-specific PNA probes on human
lymphocytes, amniocytes, spermatozoa as well as on isolated
oocytes and blastomeres. Multicolor peptide nucleic acid-fluorescence
in situ hybridization (PNA-FISH) protocols have been
described for the identification of several human chromosomes,
indicating that PNAs could become a powerful tool for in
situ chromosomal investigation.
[Back to top]
Candidate Circulating Biomarkers for the Cardiovascular Disease
Continuum
O. Dotsenko, J. Chackathayil, J.V. Patel, P.S.
Gill and G.Y.H. Lip
The early identification of susceptibility to adverse cardiovascular
outcomes and risk stratification amongst asymptomatic individuals,
as well as amongst those with overt disease continues to be
one of the major priorities of clinically-orientated research
in the field of atherothrombosis. Available data from epidemiological
studies indicate that traditional risk factors do not fully
explain the predisposition to cardiovascular disease, its
dynamics in different population groups and treatment responses.
The pressing need for the development and clinical implementation
of new markers of atherothrombotic disease has fuelled rapidly
expanding research into cardiac biomarkers.
This review outlines the main principles of biomarker qualification
that have entered clinical practice, as well as an overview
of the de-velopment of targeted biomarkers across the cardiovascular
“continuum”. We discuss in detail the evidence
from epidemiological and clinical studies advocating the potential
clinical use of the most promising candidate plasma biomarkers
(more specifically, C-reactive protein, coagulation and inflammatory
mediators and natriuretic peptides). Such an application of
biomarkers to aid clinical risk assessment would be important
in our efforts to improve risk stratification of subjects
at risk of cardiovascular events.
[Back to top]
Conus Venoms - A Rich Source of Peptide-Based Therapeutics
T.S. Han, R.W. Teichert, B.M. Olivera and
G. Bulaj
Over two decades of research on venom peptides derived from
cone snails (“conopeptides or conotoxins”) has
led to several compounds that have reached human clinical
trials, most of them for the treatment of pain. Remarkably,
none of the conopeptides in clinical development mediate analgesia
through the opioid receptors, underlying the diverse and novel
neuropharmacology evolved by Conus snails. These
predatory animals produce an estimated ~100,000 distinct conotoxins,
a vast majority yet to be discovered and characterized. The
conopeptides studied to-date in animal models, have exhibited
antinociceptive, antiepileptic, neuroprotective or cardioprotective
activities. Screening results also suggest applications of
conotoxins in cancer, neuromuscular and psychiatric disorders.
Additional potentially important applications of conotoxin
research are the discovery and validation of new therapeutic
targets, also defining novel binding sites on already validated
molecular targets. As the structural and functional diversity
of conotoxins is being investigated, the Conus venoms
continue to surprise with the plethora of neuropharmacological
compounds and potential new therapeutics. This review summarizes
recent efforts in the discovery of conopeptides, and their
preclinical and clinical development.
[Back to top]
Peptides Targeting Voltage-Gated Calcium Channels
R.S. Norton and S.I. McDonough
Many peptides are potent and highly selective blockers or
modulators of calcium channel function, and as such are valuable
pharmacological tools and potentially valuable leads for the
development of human therapeutics. Cone shells and spiders
are rich sources of such peptides, although they are also
found in scorpions and insects. In this article we compare
the amino acid sequences of toxins active against calcium
channels and describe their three-dimensional structures and
structure-function relationships. Certain structural motifs,
in particular the inhibitor cystine knot, prove to be quite
common amongst this class of toxins. Aspects of the pharmacology
and physiology of these toxins in mammalian systems are also
discussed, with an emphasis on their application in the treatment
of chronic pain. We then consider the prospects for peptide-based
therapeutics targeting calcium channels for this and other
indications, including the development of non-peptide (peptidomimetic)
compounds based on a detailed understanding of toxin structure-function
relationships.
[Back to top]
Animal Peptides Targeting Voltage-Activated Sodium Channels
B. Billen, F. Bosmans and J. Tytgat
Throughout millions of years of evolution, nature has supplied
various organisms with a massive arsenal of venoms to defend
themselves against predators or to hunt prey. These venoms
are rich cocktails of diverse bioactive compounds with divergent
functions, extremely effective in immobilizing or killing
the recipient. In fact, venom peptides from various animals
have been shown to specifically act on ion channels and other
cellular receptors, and impair their normal functioning. Because
of their key role in the initiation and propagation of electrical
signals in excitable tissue, it is not very surprising that
several isoforms of voltage-activated sodium channels are
specifically targeted by many of these venom peptides. Therefore,
these peptide toxins provide tremendous opportunities to design
drugs with a higher efficacy and fewer undesirable side effects.
This review puts venom peptides from spiders, scorpions and
cone snails that target voltage-activated sodium channels
in the spotlight, and addresses their potential therapeutical
applications.
[Back to top]
Animal Toxins Acting on Voltage-Gated Potassium Channels
S. Mouhat, N. Andreotti, B. Jouirou and
J-M. Sabatier
Animal venoms are rich natural sources of bioactive compounds,
including peptide toxins acting on the various types of ion
channels, i.e. K+, Na+,
Cl- and Ca2+.
Among K+ channel-acting toxins,
those selective for voltage-gated K+
(Kv) channels are widely represented and have been isolated
from the venoms of numerous animal species, such as scorpions,
sea anemones, snakes, marine cone snails and spiders. The
toxins characterized hitherto contain between 22 and 60 amino
acid residues, and are cross-linked by two to four disulfide
bridges. Depending on their types of fold, toxins can be classified
in eight structural categories, which showed a combination
of β-strands,
helices, or a mixture of both. The main architectural motifs
thereof are referred to as
α/β
scaffold and inhibitor cystine knot (ICK). A detailed analysis
of toxin structures and pharmacological selectivities indicates
that toxins exhibiting a similar type of fold can exert their
action on several subtypes of Kv channels, whereas a particular
Kv channel can be targeted by toxins that possess unrelated
folds. Therefore, it appears that the ability of structurally
divergent toxins to interact with a particular Kv channel
relies onto a similar spatial distribution of amino acid residues
that are key to the toxin-channel interaction (rather than
the type of toxin fold). The diversity of Kv channel blockers
and their therapeutic value in the potential treatment of
a number of specific human diseases, especially autoimmune
disorders, inflammatory neuropathies and cancer, are reviewed.
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