Current Pharmaceutical Design, Volume 11, No. 19, 2005
Contents
Plants
as Sources of Therapeutic Proteins
Executive
Editor: Schuyler S. Korban
Editorial Pp.2403-2403
Schuyler S. Korban
Medicinal Plants for the Prevention and
Treatment of Bacterial Infections Pp.2405-2427
G.B. Mahady
Secretory IgA Antibodies from Plants Pp.2429-2437
K.L. Wycoff
Recent Progress in Plantibody Technology Pp.2439-2457
E. Stoger, M. Sack, L.
Nicholson, R. Fischer and P. Christou
Producing Human Therapeutic Proteins in
Plastids Pp.2459-2470
J.M. Nugent and S.M.
Joyce
General Articles
Pharmacological Management of Acutely
Agitated Schizophrenic Patients
Pp.2471-2477
L. San, B. Arranz and
R. Escobar
Current Status and Perspectives in
Ceramide-Targeting Molecular Medicine Pp.2479-2487
Hirofumi Sawai,
Naochika Domae and Toshiro Okazaki
Biotechnological Engineering of Heparin/Heparan
Sulphate: A Novel Area of Multi-Target Drug Discovery Pp.2489-2499
Marco Rusnati, Pasqua
Oreste, Giorgio Zoppetti, and Marco Presta
Modulation of Collagen Turnover in
Cardiovascular Disease
Pp.2501-2514
J.A. Rodriguez-Feo,
J.P.G. Sluijter, D.P.V. de Kleijn, G. Pasterkamp
The Puzzle of Asthma Treatment: Animal Models
to Genetic Studies
Pp.2515-2524
T. S. Frode and Y. S.
Medeiros
Tumour Re-Differentiation Effect of Retinoic
Acid: A Novel Therapeutic Approach for Advanced Thyroid Cancer Pp.2525-2531
Sabrina M. Coelho, Mario Vaisman & Denise P. Carvalho
Abstracts
[Back to top] Editorial
Schuyler S. Korban
Plants have long been important sources of naturally-derived compounds
that have contributed to human health and well-being. These natural products
have contributed to the development of new drugs for treatment of myriad of
ailments and serious human diseases. Some of the herbal extracts and
phytomedicines are used primarily in developing countries and in Europe, and
they are gaining more acceptance by the general public in the United States as
well. Among the recent examples of plant-purified chemical compounds are
quinine from Cinchona for the treatment of malaria, reserpine from Rauvolfia
serpentina for the treatment of hypertension, and more recently taxol
from Taxus brevifolia species for the treatment of ovarian
cancer. These compounds followed the same method of development and evaluation
as other pharmaceutical drugs. There are now increased efforts to evaluate and
screen thousands of plant species for identifying those with antibacterial
activities. The review by Dr. Mahady [1] will focus on antibacterial activities
of those plant species for which there are in vitro, in vivo, clinical
data, and plausible mechanisms of action.
The field of molecular biology has provided scientists with powerful
tools for isolating, cloning, and characterizing myriad genes controlling
useful traits in all living organisms. This ever-exploding information of
fundamental genomic biology in combination with the tools of genetic
engineering have opened up new opportunities for utilizing plants as viable and
low-cost “biological reactors” or bioreactors for the production of high-value
therapeutic proteins and medicinal products.
Recombinant monoclonal antibodies were first made in transgenic plants
more than 15 years ago. Since then, there have been dozens of published reports
describing the expression of antibodies in plants and discussing their
potential and actual application as therapeutic and prophylactic agents for the
treatment or prevention of infectious diseases. Dr. Wycoff [2] provides a
review of the expression of IgA and Secretory IgA (SIgA) antibodies in plants
and sheds light on the unique challenges and potential applications of this
antibody type. While, Stoger et al. [3] describe recombinant antibody
(plantibody) production, biochemical constraints, and improving product yield
in plants. Recently, the use of plastid transformation technology that allows
for significantly higher levels of expression of therapeutic proteins, thus
minimizing down-stream processing costs, offers a powerful system for
production of plant-based protein therapies, and is reviewed by Nugent and
Joyce [4].
References
[1] Mahady GB. Medicinal
plants for the prevention and treatment of bacterial infections. Curr Pharm
Design 2005; 11(19): 2405-2427.
[2] Wycoff KL. Secretory
IgA antibodies from plants. Curr Pharm Design 2005; 11(19): 2429-2437.
[3] Stoger E, Stack M,
Nicholson L, Fischer R, Christou P. Recent progress in plantibody technology.
Curr Pharm Design 2005; 11(19): 2439-2457.
[4] Nugent JM, Joyce SM.
Producing human therapeutic proteins in plastids. Curr Pharm Design 2005;
11(19): 2459-2470.
[Back
to top] Medicinal
Plants for the Prevention and Treatment of Bacterial Infections
G.B. Mahady
Infectious diseases are a significant cause of morbidity and mortality worldwide,
accounting for approximately 50% of all deaths in tropical countries and as
much as 20% of deaths in the Americas. Despite the significant progress made in
microbiology and the control of microorganisms, sporadic incidents of epidemics
due to drug resistant microorganisms and hitherto unknown disease-causing
microbes pose an enormous threat to public health. These negative health trends
call for a global initiative for the development of new strategies for the
prevention and treatment of infectious disease. For over 100 years chemical
compounds isolated from medicinal plants have served as the models for many
clinically proven drugs, and are now being re-assessed as antimicrobial agents.
The reasons for this renaissance include a reduction in the new antibacterial
drugs in the pharmaceutical pipeline, an increase in antimicrobial resistance,
and the need of treatments for new emerging pathogens. Literally thousands of
plant species have been tested against hundreds of bacterial strains in
vitro and many medicinal plants are active against a wide range of gram
positive and gram negative bacteria. However, very few of these medicinal plant
extracts have been tested in animal or human studies to determine safety and
efficacy. This review focuses on the medicinal plants and bacteria for which
there is significant published in vitro, in vivo and clinical data
available. The examples provided in this review indicate that medicinal plants
offer significant potential for the development of novel antibacterial
therapies and adjunct treatments (i.e. MDR pump inhibitors).
[Back
to top] Secretory IgA Antibodies from Plants
K.L. Wycoff
Secretory IgA (SIgA) is the antibody type produced in both mammals and
birds that protects the body from infection at mucosal surfaces. While
monoclonal IgG antibodies, particularly those against tumor antigens, have
received a great deal of attention, both scientific and commercial, as
immunotherapeutic agents, the potential of SIgA antibodies has only recently
begun to be exploited. Part of the reason for this is that SIgA production in
vivo normally requires the cooperation of two different cell types, and
single animal cell systems for monoclonal SIgA production are inefficient.
Transgenic plants are currently the most productive and economical system for
making SIgA. The only monoclonal SIgA to be tested therapeutically in a human
clinical trial is a product called CaroRx, made in transgenic tobacco, which is
designed to block adherence to teeth of the bacteria that causes cavities. This
antibody accumulates to high levels in the leaves of tobacco, where it is
located primarily in the endoplasmic reticulum. The antibody can be efficiently
purified using the affinity reagent protein G. Topical oral treatment in human
subjects was safe and effective. Characterization of the expression, secretion,
purification and therapeutic use of this antibody serves as a model for
additional plant-made therapeutic SIgA antibodies under development.
[Back
to top] Recent
Progress in Plantibody Technology
E. Stoger, M. Sack, L. Nicholson, R. Fischer and P.
Christou
Antibodies are an important class of proteins that can be used for the
prevention, treatment and diagnosis of many diseases. Consequently, there is an
intense and growing demand for recombinant antibodies, placing immense pressure
on current production capacity which is based largely on microbial cultures and
mammalian cells. Alternative systems for cost effective antibody production
would be very welcome, and plants are now gaining widespread acceptance as
green bioreactors with advantages in terms of cost, scalability and safety.
Several plant-produced antibodies (plantibodies) are undergoing clinical trials
and the first commercial approval could be only a few years away. The
performance of the first generation of products has been very encouraging so
far. In terms of product authenticity, differences in glycosylation between
plantibodies and their mammalian counterparts have been defined, and the
scientific evaluation of any possible consequences is underway. Ongoing studies
are addressing the remaining biochemical constraints, and aim to further
improve product yields, homogeneity and authenticity, particularly where the antibody
is intended for injection into human patients. A remaining practical challenge
is the implementation of large-scale production and processing under good
manufacturing practice conditions that are yet to be endorsed by regulatory
bodies. The current regulatory uncertainty and the associated costs represent
an entry barrier for the pharmaceutical industry. However, the favourable
properties of plants are likely to make the plant systems a useful alternative
for small, medium and large scale production throughout the development of new
antibody-based pharmaceuticals.
[Back
to top] Producing
Human Therapeutic Proteins in Plastids
J.M. Nugent and S.M. Joyce
Plastid transformation technology is set to become a major player in
the production of human therapeutic proteins. Protein expression levels that
can be achieved in plant plastids are hundreds of times greater than the
expression levels generally obtained via nuclear transformation.
Plastids can produce human proteins that are properly folded and are
biologically active. Effective protein purification strategies and strategies
that can achieve inducible plastid gene expression are being developed within
the system. Plastid transformation technology has been extended to edible plant
species, which could minimize down-stream processing costs and raises the
possibility of “edible protein therapies”. The system is limited by the fact
that plastid-produced proteins are not glycosylated and that, at the moment, it
can be difficult to predict protein stability within the plastid. The high
level of protein expression that can be obtained in plastids could make it
possible to produce high-value therapeutic proteins in plants on a scale that
could be accommodated in contained glasshouse facilities and still be
economically viable. Growing plastid-transformed plants under contained
conditions, and coupled with the level of bio-safety conferred by maternal
inheritance of plastid transgenes, would address many of the social and
environmental concerns relating to plant based production of human therapeutic
proteins.
[Back
to top] Pharmacological
Management of Acutely Agitated Schizophrenic Patients
L. San, B. Arranz and R. Escobar
Agitation is commonly seen in acute schizophrenic patients and core
symptoms include a wide range of symptom. It requires rapid and effective
treatment approaches in order to protect patient and caregiver from potential
injury. Clinician’s decision of pharmacological treatment should be
individualized to the needs and circumstances of the patient. Benzodiazepines,
typical antipsychotics, and combinations of typical antipsychotics and
benzodiazepines have been widely used as treatment options. Atypical
antipsychotics have clear advantages over the typical drugs as they generally
show a much better safety and tolerability profile, particularly to EPS and
related side effects, however clinical perception regarding efficacy in
treating acutely agitated psychotic patient is controversial. New intramuscular
atypical antipsychotic formulations offer evidence of being at least as
effective as typical antipsychotics in controlling agitation. Therefore, they
should be considered as first line therapy in agitated schizophrenic patients.
[Back
to top] Current Status and Perspectives in Ceramide-Targeting Molecular
Medicine
Hirofumi Sawai,
Naochika Domae and Toshiro Okazaki
Ceramide is not only structurally but also functionally a key molecule
in diverse kinds of sphingolipids. In the past decade, ceramide has been shown
to be of crucial significance in several cell functions including apoptosis,
cell growth, senescence, and cell cycle control. Among them, the role of
ceramide in apoptosis induction has extensively been studied, and
ceramide-targeting molecular medicine for apoptosis-based diseases such as
malignant tumors, atherosclerosis and neurodegenerative disorders appears to
come out to the clinical field. We here describe the recent advances in
research of ceramide-mediated apoptosis signaling. We also show the relation of
ceramide level through regulation of ceramide-related enzymes
(sphingomyelinase, ceramidase, sphingomyelin synthase and glucosylceramide
synthase) with diseases such as cancer, leukemia, bacterial infections, AIDS,
Alzheimer’s disease, atherosclerosis, diabetes mellitus and atopic dermatitis.
The strategies to construct the ceramide-targeting medicine for intractable
diseases such as cancer and leukemia are discussed.
[Back
to top] Biotechnological
Engineering of Heparin/Heparan Sulphate: A Novel Area of Multi-Target Drug
Discovery
Marco Rusnati, Pasqua
Oreste, Giorgio Zoppetti, and Marco Presta
Heparin is a sulphated glycosaminoglycan currently used as an
anticoagulant and antithrombotic drug. It consists largely of 2-O-sulphated
IdoA ® N, 6-O-disulphated GlcN disaccharide units. Other
disaccharides containing unsulphated IdoA or GlcA and N-sulphated or N-acetylated
GlcN are also present as minor components. This heterogeneity is more
pronounced in heparan sulphate (HS), where the low-sulphated disaccharides are
the most abundant.
Heparin/HS bind to a variety of biologically active polypeptides,
including enzymes, growth factors and cytokines, and viral proteins. This
capacity can be exploited to design multi-target heparin/HS-derived drugs for
pharmacological interventions in a variety of pathologic conditions besides
coagulation and thrombosis, including neoplasia and viral infection.
The capsular K5 polysaccharide from Escherichia coli has the
same structure as the heparin precursor N-acetyl heparosan. The
possibility of producing K5 polysaccharide derivatives by chemical and
enzymatic modifications, thus generating heparin/HS-like compounds, has been
demonstrated. These K5 polysaccharide derivatives are endowed with different
biological properties, including anticoagulant/antithrombotic, antineoplastic,
and anti-AIDS activities.
Here, the literature data are discussed and the possible therapeutic
implications for this novel class of multi-target “biotechnological heparin/HS”
molecules are outlined.
[Back
to top] Modulation of Collagen Turnover in Cardiovascular Disease
J.A. Rodriguez-Feo,
J.P.G. Sluijter, D.P.V. de Kleijn, G. Pasterkamp
Collagen fibers are the most abundant components of the extracellular
matrix in arteries and myocardium. Disturbances in the collagen turnover
(synthesis and degradation) have been linked to inflammatory diseases including
cardiovascular pathological syndromes. In the myocardium, changes in collagen
turnover may result in ventricle dilatation and subsequent contractile
dysfunction. In arteries, collagen synthesis and degradation are associated
with the progression of atherosclerotic disease and intimal hyperplasia
following injury.
Collagen synthesis is tightly regulated at several levels: synthesis of
procollagens, suitable folding of polypeptides, secretion and cross-linking of
mature fibers. On the other hand, degradation of newly synthesised procollagen
and mature collagen fibers depends on the action of Matrix-Metalloproteinases
(MMPs).
The major role of collagen turnover in cardiovascular disorders has
stimulated the search for pharmacological agents that interfere with collagen
turnover at different levels. These drugs can theoretically act through
modulation of the synthesis of procollagens or by interference with their
post-translational modifications. Another group of pharmacological agents
inhibit collagen breakdown (MMP inhibitors). Beneficial effects of compounds
that target collagen metabolism have been reported. Unfortunately, many of these
compounds also give rise to serious adverse effects due to interference with
vital biological processes in which collagen plays an important role.
In this paper, we will review cardiovascular diseases in which altered
local collagen turnover is a key feature. Subsequently, the effect of compounds
that have been developed and tested to modulate collagen synthesis,
cross-linking or breakdown will be discussed.
[Back
to top] The Puzzle of Asthma Treatment: Animal Models to Genetic Studies
T. S. Frode and Y. S. Medeiros
The recognition that asthma is an inflammatory disease opens a new
field to find effective models for the evaluation and development of new drugs.
In this scenario, many novel candidate molecules have been shown to work
perfectly in animal models, but not in clinical studies. Ancillary models are
reviewed in association with the findings obtained in either transgenic or
knockout mice. In parallel, genetic studies in animal models and human
populations have identified several genes that are asthma-related. Knowledge of
these recent findings, in parallel with pharmacogenomic studies will be
necessary to direct new strategies for the development of novel drugs to treat
subgroups of patients with asthma.
[Back
to top] Tumour
Re-Differentiation Effect of Retinoic Acid: A Novel Therapeutic Approach for
Advanced Thyroid Cancer
Sabrina M. Coelho, Mario Vaisman & Denise P. Carvalho
Although well-differentiated thyroid carcinomas are usually curable by
the combined effects of surgery, radioiodine ablation and thyroid stimulating
hormone (TSH) suppressive therapy, recurrence develops in 20-40% of patients.
During tumour progression, cellular de-differentiation occurs in up to 30% of
cases and is usually accompanied by more aggressive growth, metastasis spread
and loss of iodide uptake. The therapeutic options for de-differentiated
thyroid cancer are limited and generally not efficient. Retinoic acids (RA) are
biologically active metabolites of vitamin A that regulate growth and
differentiation of many cell types, by binding to specific nuclear receptors:
the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Recent
studies have shown that RA can induce in vitro re-differentiation of
thyroid carcinoma cell lines, as suggested by increased expression of the
sodium/iodide symporter (NIS), type I iodothyronine deiodinase, alkaline
phosphatase and by the increment of cellular 131I uptake. In
addition to re-differentiating effects, RA also exert anti-proliferative
actions, as the inhibition of mitosis and the induction of apoptosis. Previous
clinical studies have shown that iodide uptake may be re-stimulated after RA in
about 20-50% of patients with radioiodine non-responsive thyroid carcinoma.
Longer follow-up of patients demonstrated that, besides iodide uptake
increment, RA can induce tumour regression or at least tumour growth
stabilisation. The therapy is generally well tolerated and the most frequent
side effects are dryness of skin and mucosa, and hypertriglyceridemia. This
paper describes the recent advances in the field of thyroid cancer therapy and
reviews the use of RA as a promising novel therapeutic tool.