Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 9, 2007
Contents
Food-Derived Bioactive Proteins and Peptides as Potential
Components of Nutraceuticals
Executive Editor: H. Meisel
Editorial Pp. 873-874
Egg Proteins and Peptides in Human Health-Chemistry,
Bioactivity and Production Pp. 875-884
Y. Mine
[Abstract]
Food-Derived Peptides and Intestinal Functions
Pp. 885-895
M. Shimizu and D.O. Son
[Abstract]
Cytotoxic and Allergenic Potential of Bioactive Proteins
and Peptides Pp. 897-920
R. Hartmann, J.-M. Wal, H. Bernard and A.-K. Pentzien
[Abstract]
Nucleoprotein-Derived and Unbound Ribonucleosides:
Bioactivity and Potential Applications Pp. 921-932
D. Martin and H. Meisel
[Abstract]
General Articles
Poly(ADP-Ribose) Polymerase Inhibitors: New Pharmacological
Functions and Potential Clinical Implications Pp.
933-962
C.A. de la Lastra, I. Villegas and S. Sánchez-Fidalgo
[Abstract]
Design of New Oxazaphosphorine Anticancer Drugs
Pp. 963-978
J. Liang, M. Huang, W. Duan, X.-Q. Yu and S. Zhou
[Abstract]
Abstracts
[Back to top]
Editorial: Food-Derived Bioactive Proteins and Peptides
as Potential Components of Nutraceuticals
In the last two decades fundamental studies have opened a
new field of research related to bioactive food components
that not only help ensure adequate nutrition, but may provide
specific health benefits [for review: 1]. Bioactive components
of food origin can be defined as substances, both nutrient
and non-nutrient, which may exert regulative activities in
the human organism beyond basic nutrition. In particular,
food-derived bioactive proteins and peptides are claimed to
be health-enhancing components used to reduce the risk of
disease or to enhance a certain physiological function.
This issue as well as the previous Volume 13, Number 8, 2007,
focuses on the advances being achieved in the research on
the biochemical properties, physiological effects, production,
safety and applications of different bioactive components,
with emphasis on milk and egg protein-derived proteins and
peptides. Bovine milk and avian eggs contain an array of bioactivities
due to proteins and peptides present in active form, such
as lysozyme, immunoglobulins, growth factors and hormones.
In addition to these fully active components, many bioactivities
are latent in that they are inactive within the protein sequence,
requiring enzymatic proteolysis for release of bioactive peptides
from protein precursors. Bovine milk is currently the main
source of a range of bioactive peptides encrypted in major
milk proteins [for review: 2]. Activated peptides may exert
quite different bioactivities, such as opioid, ACE-inhibitory,
immunomodulatory, antimicrobial, mineral binding, antimutagenic
and cytomodulatory effects.
In the first article, Mine [3] focuses on biological activities
of proteins and peptides derived from avian egg, and review
their applications in the food and pharmaceutical industries.
Several biological activities have been associated with egg
components, including anti-microbial, immunomodulatory, anti-cancer
and anti-hypertensive activities, anti-adhesive and anti-oxidant
properties, protease inhibitors, nutrient bioavailability
and functional lipids.
In the paper of Shimizu and Dong Ok Son [4] food-derived peptides
and intestinal functions are discussed with very interesting
considerations. Although dietary peptides are mostly hydrolyzed
by digestive enzymes in the intestinal tract, some could be
absorbed intact and act in their target organs. Moreover,
the intestine is the main target site for functional peptides,
i.e. intestine-modulatory peptides can express their functions
in the intestinal tract or modulate intestinal epithelial
cell functions. These modulatory peptides are showing promising
functions in preventing intestinal diseases.
The article of Hartmann and Coworkers [5] deals with the assessment
of cytotoxic and allergenic potential of bioactive proteins
and peptides. When evaluating cytotoxic proteins and peptides
of plant and animal origin it is evident that some of these
compounds seem to be most effective towards malignant cells
leading to the assumption that a cancer protective effect
could exist for such bioactive proteins and peptides. Some
peptide fragments may conserve part of the allergenicity of
the native protein and thus can also be considered as allergens.
The data presented on the relationship between the structure
of food proteins and peptides and their allergenicity shows
the difficulty in trying to assess the “non-allergenicity”
of products derived from an allergenic source, even if the
process used involved extensive hydrolysis of the native protein.
Finally, the paper of Martin and Meisel [6] reviews nucleoprotein-derived
and naturally occurring free ribonucleosides as bioactive
compounds, including their effects in human cell systems and
their functions as marker molecules in cancer disease. Naturally
occurring and chemically modified ribonucleosides have interesting
bioactive effects, e.g. the ability to enhance gut growth
and maturation, to increase iron absorption and to induce
apoptosis in human cells. Chemically modified ribonucleosides
have already found interesting applications as pharmaceutically
active compounds in the treatment of different illnesses.
Regarding therapeutic and pharmaceutical aspects, further
studies are required to evaluate the bioactive efficacy of
indigenous ribonucleosides.
There has been a growing interest in using biologically active
proteins and peptides for application within the food industry.
Accordingly, food researchers are presently considering different
bioactive substances of food origin as health enhancing ingredients
for use in foods commonly referred to as functional foods
or nutraceuticals [1, 2]. Furthermore, food-derived proteins
and peptides, which can be manufactured on an industrial scale,
have already been considered for interesting applications
as medical foods or pharmaceutical preparations. Medical food
products and drugs are designed to supply missing nutrients
to prevent, treat or cure a disease where pharmacologically
active compounds are needed. Food producers are forbidden
to claim that their products can cure, prevent or treat a
disease. They can, however, make health claims about their
products, providing they are able to produce sufficient scientific
evidence.
Even if food and pharmaceutics are to be treated as separate
entities, with different purposes and modes of action, the
research on bioactive proteins and peptides has some common
objectives:
- providing evidence that the constituent is present in a
quantity and in a form needed to exert a specific function,
- basing the reduction of disease risk claims as well as pharmaceutical
effects indicated on the label on human studies, having a
scientific valid design for showing a persistent effect of
the food or pharmaceutical preparation,
- evaluating the risks the consumption of the products could
pose to public health, including allergic potential.
Regarding the discovery of novel peptide drugs, the chemical
properties of food-derived peptides (and proteins) can be
readily modified in systematic ways for drug design and development.
It is worth noting that very small changes in structure can
lead to dramatic changes in bioactive potency and function,
and that peptides are generally less toxic than other organic
'natural molecules'.
Future research should focus on establishing novel production
technologies and understanding the interaction of different
bioactive proteins and peptides with multiple components during
production and within a complex food of an overall diet. There
are many unknown factors regarding to physicochemical and
biological interactions of bioactive ingredients, which may
result in inactivation or in synergisms and antagonisms. Understanding
the mechanisms of possible interactions is important to develop
an adequate packaging system, like microencapsulation, to
enable the improved delivery and protection of bioactive ingredients.
Research continues to discover novel bioactive proteins /peptides,
functions and health benefits - all of which reveal the striking
potential for natural selection through evolution to produce
food molecules that act beyond simply providing nutrients.
Discovering these benefits and potential applications remains
a great challenge for both nutrition research and pharmaceutical
design.
References
[1] Mine Y, Shahidi F. In: Mine Y, Shahidi F Eds, Nutraceutical
proteins and peptides in health and disease: an overview.
Boca Raton, CRC Press Taylor & Francis Group. 2006; 3-9.
[2] Meisel H. Biochemical properties of peptides encrypted
in bovine milk proteins. Curr Med Chem 2005; 12: 1905-1919.
[3] Mine Y. Egg proteins and peptides in human health - chemistry,
bioactivity and production. Curr Pharm Des 2007; 13(9): 875-884.
[4] Shimizu M, Dong Ok Son. Food-derived peptides and intestinal
functions. Curr Pharm Des 2007; 13(9): 885-895.
[5] Hartmann R, Pentzien A-K, Wal J-M, Bernard H. Cytotoxic
and allergenic potential of bioactive proteins and peptides.
Curr Pharm Des 2007; 13(9): 897-920.
[6] Martin D, Meisel H. Nucleoprotein-derived and unbound
ribonucleosides: bioactivity and potential applications. Curr
Pharm Des 2007; 13(9): 921-932.
Hans Meisel, Prof. Dr.
Institute of Dairy Chemistry and Technology
Federal Research Centre for Nutrition and Food (BfEL) - Location
Kiel
Hermann-Weigmann-Str. 1
D-24103 Kiel
Germany
E-mail: hans.meisel@bfel.de
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Egg Proteins and Peptides in Human Health-Chemistry,
Bioactivity and Production
Y. Mine
Egg is the largest biological cell known which originates
from one cell division and is composed of various important
chemical substances that form the basis of life. The avian
egg is an important source of nutrients, containing all of
the proteins, lipids, vitamins, minerals and growth factors
required by the developing embryo, as well as a number of
defence factors to protect against bacterial and viral infection.
This review mainly focuses on biological activities of proteins
and peptides derived from egg components. Several biological
activities have now been associated with egg components, including
novel anti-microbial activities, anti-adhesive properties,
immunomodulatory, anti-cancer, and anti-hypertensive activities,
anti-oxidant properties, protease inhibitors, nutrient bioavailability
and functional lipids, highlighting the importance of egg
and egg components in human health, and disease prevention
and treatment.
[Back to top]
Food-Derived Peptides and Intestinal Functions
M. Shimizu and D.O. Son
The intestines are an important organ responsible for nutrient
absorption, metabolism and recognition of food signals. The
organ also acts as a physical and biological barrier against
harmful substances including food pathogens and environmental
chemicals. Food-derived peptides with a variety of physiological
functions have been discovered in the past several decades.
Although dietary peptides would mostly be hydrolyzed by digestive
enzymes in the intestinal tract, possibly losing their biological
functions during this step, some could be absorbed intact
and act in their target organs. The intestines are also one
of the targets for functional peptides. The intestine-modulatory
peptides can be classified into two categories: (1) peptides
that express their functions in the intestinal tract and (2)
peptides that modulate intestinal epithelial cell functions.
The 1st group includes peptides that regulate the
intestinal absorption of nutrients. Enhancing mineral absorption
by casein phosphopeptides, and suppressing dietary cholesterol
absorption by soybean peptides are typical examples. The 2nd
group includes such glutamine-containing peptides as Ala-Gln
that show interesting properties in preventing and/or repairing
damage caused by oxidative stress and inflammatory reactions.
We have found that carinosine (β-Ala-His)
suppressed the secretion of such inflammatory cytokines as
IL-8 in human intestinal epithelial cells, suggesting its
anti-inflammatory function in the intestines. Peptides that
modulate such intestinal immune functions as secretory IgA
production and cytokine secretion, and opioid peptides regulating
intestinal motility are also included in this group. These
intestine-modulatory peptides would be useful as ingredients
of future functional foods to prevent lifestyle-related diseases
and promote gut health.
[Back to top]
Cytotoxic and Allergenic Potential of Bioactive Proteins
and Peptides
R. Hartmann, J.-M. Wal, H. Bernard and A.-K. Pentzien
This review article deals with the assessment of cytotoxic
and allergenic potential of bioactive proteins and peptides.
It is evident that ‘novel’ foods or nutraceuticals
containing bioactive proteins and peptides must fulfill their
proposed “health claim”. Furthermore, there is
a need to assess their potential to exert adverse effects
before they can be made widely available to consumers. A brief
overview of compounds (i.e. proteins and peptides of animal
and plant origin) and mechanisms involved in cytotoxic and
allergenic (adverse) reactions is given along with some recent
results obtained from ongoing studies.
There are numerous proteins and peptides of plant and animal
origin that are known to exhibit cytotoxic effects. There
is evidence that many cytotoxic compounds described in the
literature exclusively affect malignant cells leading to the
assumption that a cancer protective effect could exist for
such bioactive proteins and peptides.
All the constituents that are responsible for the allergenicity
of foods (as well as of pollens) are proteinaceous in nature.
Some protein breakdown products, i.e. peptide fragments, may
conserve part of the allergenicity of the native protein and
thus can also be considered as allergens. The molecular basis
of IgE recognition underlying cow’s milk protein allergy
is described. Some results from studies on volunteers fed
caseinophosphopeptides or potentially hypotensive milk protein
hydrolysates illustrate the major difference between allergenicity
and immunogenicity. The data presented on the relationship
between the structure of food proteins and peptides and their
allergenicity shows the difficulty in trying to assess the
“non-allergenicity” of products derived from an
allergenic source, even if the process used involved extensive
hydrolysis of the native protein(s). A ‘weight of evidence
approach’ for assessing the potential allergenicity
of a novel protein with no history of prior allergenicity
is also presented with regard to the current EU Regulations.
[Back to top]
Nucleoprotein-Derived and Unbound Ribonucleosides:
Bioactivity and Potential Applications
D. Martin and H. Meisel
Naturally occurring and chemically modified ribonucleosides
have interesting bioactive effects. Dietary ribonucleosides
are ingested mainly as nucleoproteins and are converted in
the course of intestinal digestion to monomeric compounds.
Different bioactive effects of dietary ribonucleosides have
been described, including the ability to enhance gut growth
and maturation and to increase iron absorption. Cytochemical
studies with human cells showed that several ribonucleosides
can induce apoptosis in human cells, and therefore may be
potentially anticancerogenic compounds. Even if suboptimal
concentrations of single bioactive nucleo compounds are available
from food, the total content of different bioactive ribonucleosides
may reach physiologically effective concentrations in
vivo where intestinal cells may represent the main target
sites of a selective apoptotic activity. Modified ribonucleosides
serve as valuable pathobiochemical marker molecules for cancer.
Chemically modified ribonucleosides have already found interesting
applications as pharmaceutically active compounds in the treatment
of different illnesses including AIDS. Regarding therapeutic
and pharmaceutical aspects, further studies are required to
evaluate the bioactive efficacy of indigenous ribonucleosides.
The findings demonstrate the great variety of potential applications
of ribonucleosides, e.g. in functional foods as well as pharmaceutical
preparations.
[Back to top]
Poly(ADP-Ribose) Polymerase Inhibitors: New Pharmacological
Functions and Potential Clinical Implications
C.A. de la Lastra, I. Villegas and S. Sánchez-Fidalgo
Poly(ADP-ribose) polymerase (PARP) comprise of a family of
enzymes which catalyses poly(ADP-ribosyl)ation of DNA-binding
proteins. To date, seven isoforms have been identified: PARP-1,
PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5 (Tankyrases),
PARP-7 and PARP-10 with structural domains and different functions.
PARP-1, the best characterised member, works as a DNA damage
nick-sensor protein that uses beta-NAD+ to form
polymers of ADP-ribose and has been implicated in DNA repair,
maintenance of genomic integrity and mammalian longevity.
The generation of free radicals, reactive oxygen species,
and peroxynitrite causes overactivation of PARP resulting
in the depletion of NAD+ and ATP and consequently
in necrotic cell death and organ dysfunction. PARP has also
been involved in the up-regulation of numerous pro-inflammatory
genes through the activation of several transcription nuclear
factors. Thus, PARP plays an important role in the pathogenesis
of several diseases, such as, stroke, myocardial infarction,
circulatory shock, diabetes, neurodegenerative disorders,
including Parkinson and Alzheimer diseases, allergy, colitis
and other inflammatory disorders. Pharmacological modulation
of PARP activity may constitute a suitable target to enhance
the cytotoxicity of certain DNA-damaging anticancer drugs.
Also, PARP inhibition may be a viable strategy to control
viral infections. This review is intended to provide an appreciation
of new pharmacological perspectives of these remarkable drugs,
summarize novel underlying mechanisms and discuss their potential
clinical implications.
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Design of New Oxazaphosphorine Anticancer Drugs
J. Liang, M. Huang, W. Duan, X.-Q. Yu and S. Zhou
The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan,
or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten)
represent an important group of therapeutic agents due to
their substantial antitumor and immunomodulating activity.
However, several intrinsic limitations have been uncounted
during the clinical use of these oxazaphosphorines, including
substantial pharmacokinetic variability, resistance and severe
host toxicity. To circumvent these problems, new oxazaphosphorines
derivatives have been designed and evaluated with an attempt
to improve the selectivity and response with reduced host
toxicity. These include mafosfamide (NSC 345842), glufosfamide
(D19575, β-D-glucosylisophosphoramide
mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567
(aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide
thiazolidine). Mafosfamide is an oxazaphosphorine analog that
is a chemically stable 4-thioethane sulfonic acid salt of
4-hydroxy-CPA. Glufosfamide is IFO derivative in which the
isophosphoramide mustard, the alkylating metabolite of IFO,
is glycosidically linked to a β-D-glucose
molecule. Phase II studies of glufosfamide in the treatment
of pancreatic cancer, non-small cell lung cancer (NCSLC),
and recurrent glioblastoma multiform (GBM) have recently completed
and Phase III trials are ongoing, while Phase I studies of
intrathecal mafosfamide have recently completed for the treatment
of meningeal malignancy secondary to leukemia, lymphoma, or
solid tumors. S-(-)-bromofosfamide is a bromine-substituted
IFO analog being evaluated in a few Phase I clinical trials.
The synthesis and development of novel oxazaphosphorine analogs
with favourable pharmacokinetic and pharmacodynamic properties
still constitutes a great challenge for medicinal chemists
and cancer pharmacologists.
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