Current Pharmaceutical Design, 2006, 12, 1637-1643 1637
1381-6128/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.
Emerging Therapeutic Potential of Whey Proteins and Peptides
A. Süha Yalçın
Department of Biochemistry, School of Medicine, Marmara University, Istanbul, Turkey
Abstract: Whey is a natural by-product of cheese making process. Bovine milk has about 3.5 % protein, 80 % of which
are caseins and the remaining 20 % are whey proteins. Whey proteins contain all the essential amino acids and have the
highest protein quality rating among other proteins. Advances in processing technologies have led to the industrial pro-
duction of different products with varying protein contents from liquid whey. These products have different biological ac-
tivities and functional properties. Also recent advances in processing technologies have expanded the commercial use of
whey proteins and their products. As a result, whey proteins are used as common ingredients in various products including
infant formulas, specialized enteral and clinical protein supplements, sports nutrition products, products specific to weight
management and mood control. This brief review intends to focus on scientific evidence and recent findings related to the
therapeutic potential of whey proteins and peptides.
Key Words: Whey proteins, α-lactalbumin, β-lactoglobulin, immunoglobulin, lactoferrin, bioactive peptide.
Whey is a natural by-product of cheese making process.
Bovine milk has about 3.5 % protein, 80 % of which are ca-
seins and the remaining 20 % are whey proteins. During
cheese manufacture when casein is removed from whole
milk, what remains is whey which contains lactose, proteins
and lipids. Advances in processing technologies have led to
the industrial production of different products with varying
protein contents from liquid whey . Table 1 lists some of
these products and their functional properties.
Recent studies have shown that whey proteins contain all
the essential amino acids and have the highest protein quality
rating among other proteins . Whey proteins are also con-
sidered to be “fast proteins” since they reach the jejunum
almost immediately, their hydrolysis within the intestine is
slower than other proteins and their digestion and absorption
occurs over a greater length of the intestine [2, 3]. Some
whey proteins have even been detected intact in the intestinal
lumen. Recent advances in processing technologies have
expanded the commercial use of whey proteins and their
products [4, 5]. As a result, whey proteins are used as com-
mon ingredients in various products including infant formu-
las, specialized enteral and clinical protein supplements,
sports nutrition products, products specific to weight man-
agement and mood control [6-8]. This brief review intends to
focus on scientific evidence and recent findings related to the
therapeutic potential of whey proteins and peptides.
Milk is a complex food containing different bioactive
molecular species. It is produced by the mammary glands to
nourish and protect the mammalian young. Milk contains
*Address correspondence to this author at the Department of Biochemistry,
School of Medicine, Marmara University, 34668, Haydarpasa-Istanbul,
Turkey; Tel: 90-216-4144733; Fax: 90-216-4181047;
essential nutrients as well as hormones, modulators and
growth factors that are capable of influencing the develop-
ment and growth of the gastrointestinal tract [9, 10]. Milk
influences other specific organs, modulates the gut micro-
flora population, provides immunological protection, im-
munoregulation and non-immune defence. Factors such as
breeding conditions, seasonal differences and geographic
variations affect milk composition. Approximate composi-
tion of milk may be given as: 87 % water, 5 % sugar (mainly
lactose), 3.5 % fat and 3.5 % proteins (casein micelles and
soluble whey proteins) and 1 % salts (minerals). The nitro-
gen content of milk is distributed among caseins, whey pro-
teins and non-protein compounds.
Caseins represent around 80 % of milk proteins. The
principal casein fractions are α-s1- and α-s2-caseins, β-
casein and κ-casein. All are conjugated proteins, most with
phosphate groups esterified to serine residues. Phosphate
groups are important for the structure of the casein micelle.
The distinguishing property of caseins is their low solubility
at pH 4.6. The high number of proline residues causes par-
ticular bending of the protein chain and inhibits the forma-
tion of close-packed, ordered secondary structures. Most of
the casein proteins exist in colloidal particles known as the
casein micelle. Casein micelles carry large amounts of highly
insoluble CaP and form a clot in the stomach for more effi-
cient nutrition . Caseins do not contain disulfide bonds.
Although the casein micelle is fairly stable, there are differ-
ent ways by which its aggregation may be induced. Chy-
mosin or rennet is most often used for enzymatic coagulation
of casein micelles. Different forms of caseins have distin-
guishing features, for example κ-casein is very resistant to
calcium precipitation and stabilizes other caseins. Rennet
cleavage eliminates the stabilizing ability of κ-casein by
forming hydrophobic (para-κ-casein) and hydrophilic (κ-
casein glycomacropeptide or caseinomacropeptide) portions.
1638 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 A. Süha Yalçın
Proteins appearing in the supernatant of milk after pre-
cipitation of casein are called whey proteins. These globular
proteins are more water soluble than caseins and are subject
to heat denaturation [9, 10].
Whey proteins are grouped as major and minor protein
fractions each with different molecular weights and critical
for healthy metabolism (Table 2). The major whey proteins
are β-lactoglobulin, α-lactalbumin, serum albumin, immu-
noglobulins and glycomacropeptide, while minor proteins
include lactoperoxidase, lactoferrin, β-microglobulin,
lysozyme, insulin-like growth factor (IGF), γ-globulins and
several other small proteins [10-12].
ß-Lactoglobulin is a major whey protein that corresponds
to approximately half of the total whey proteins in bovine
milk. It is a noncovalently linked dimer that has two internal
disulfide bonds and one free thiol group. It binds calcium
and zinc and has partial sequence homology to retinol bind-
ing proteins. ß-Lactoglobulin has numerous binding sites for
minerals, fat-soluble vitamins and lipids.
α-Lactalbumin is another major whey protein that makes
up 25 % of total bovine whey protein. It is a calcium binding
protein that enhances calcium absorption and is a rich source
of lysine, leucine, threonine, tryptophan and cystine. α-
Lactalbumin is specifically produced during lactation in the
mammary epithelial cells and plays an essential role in milk
synthesis. It is one of the few proteins that remains intact
Serum albumin and immunoglobulins are blood proteins
that become incorporated into milk and are recoverable as
whey proteins. Serum albumin binds fatty acids as well as
other small molecules. Immunoglobulins include IgG1,
IgG2, IgA and IgM. Bovine immunoglobulins have been put
forward as possible effective means of preventing and com-
Glycomacropeptide, the glycosylated portion of caseino-
macropeptide, is present in sweet whey formed after cleav-
age of κ-casein by rennin [13, 14]. This protein is absent
from acid whey that is formed when caseins are precipitated
by lowering the pH to 4.6. Glycomacropeptide is a powerful
stimulator of cholecystokinin which is an appetite suppress-
ing hormone that has essential roles relating to gastrointesti-
nal function. In addition to being a regulator of food intake,
cholecystokinin stimulates gallbladder contraction and bowel
motility, regulates gastric emptying and stimulates the re-
lease of enzymes from the pancreas. Glycomacropeptide
alters pigment production in melanocytes, may act as a pre-
biotic and has immunomodulatory action .
Table 1. Typical Composition of Whey Products and their Functional Properties
Product Typical Composition Functional Properties
Sweet whey powder Protein: 11.0 % - 14.5 %
Lactose: 63.0 % - 75.0
Fat: 1.0 % - 1.5 %
Ash: 8.2 % - 8.8 %
Moisture: 3.5 % - 5.0 %
Low protein source
Dairy flavor and solids
Acid whey powder Protein: 11.0 % - 13.5 %
Lactose: 61.0 % - 70.0
Fat: 0.5 % - 1.5 %
Ash: 9.8 % - 12.3 %
Moisture: 3.5 % - 5.0 %
Low protein source
Dairy flavor and solids
Whey protein concentrate
(34 % protein)
Protein: 34.0 % - 36.0 %
Lactose: 48.0 % - 52.0
Fat: 3.0 % - 4.5 %
Ash: 6.5 % - 8.0 %
Moisture: 3.0 % - 4.5 %
Mild dairy flavor
Color and flavor development
Whey protein concentrate
(80 % protein)
Protein: 80.0 % - 82.0 %
Lactose: 4.0 % - 8.0
Fat: 4.0 % - 8.0 %
Ash: 3.0 % - 4.0 %
Moisture: 3.5 % - 4.5 %
High protein source
Whey protein isolate Protein: 90.0 % - 92.0 %
Lactose: 0.5 % - 1.0
Fat: 0.5 % - 1.0 %
Ash: 2.0 % - 3.0 %
Moisture: 4.5 %
High protein source
Adapted from .
Emerging Therapeutic Potential of Whey Proteins and Peptides Current Pharmaceutical Design, 2006, Vol. 12, No. 13 1639
Lactoperoxidase and lactoferrin are minor whey proteins.
The lactoperoxidase system inactivates a broad spectrum of
microorganisms through an enzymatic reaction . The
reaction involves hydrogen peroxide and thiocyanate which
together with the enzyme constitute the lactoperoxidase sys-
tem. The lactoperoxidase system is a major part of the anti-
bacterial activity of milk. Lactoferrin is a member of the
transferrin gene family with metal binding properties [16,
17]. It is a 78 kDa glycoprotein made up of a single poly-
peptide chain and is linked to two glycans by N-glycosidic
linkages. Metals that are bound by lactoferrin are mainly
, but Cu
are bound as well. Lac-
toferrin is important for the delivery of essential metals to
the newborn and is considered to be an important component
of the non-specific immune system. Lactoferrin plays a stra-
tegic role in the first line of defense against many pathogens
that tend to enter the body via mucosa. It is present in several
mucosal secretions such as tears, saliva, seminal and vaginal
THERAPEUTIC USE OF WHEY PROTEINS AND
Whey proteins of special therapeutic importance are α-
lactalbumin, β-lactoglobulin, bovine serum albumin, immu-
noglobulins, lactoferrin and lactoperoxidase. These proteins
exhibit different biological activities and are used as ingredi-
ents in different forms of pharmaceuticals, nutraceuticals and
cosmeceuticals [5-7, 12]. Additionally, specific digestion
products of milk proteins identified as bioactive peptides
have diverse biological activities [18-20]. The bioactive
peptide sequences are in an inactive state inside the polypep-
tide chain of the intact whey protein. Peptides released dur-
ing intestinal digestion of whey proteins may be involved in
the regulation of nutrient entry as well as postprandial me-
tabolism via stimulation of hormone secretion. Therapeutic
benefits of whey proteins can also result from bioactive pep-
tide production during fermentation . Infant formula de-
velopment has been a long lasting effort to create a substitute
for mother’s milk. It is aimed to approach the nutrient com-
position of human breast milk using bovine milk as raw ma-
terial. However, the protein composition of human milk dif-
fers both quantitatively and qualitatively from that of bovine
milk . The use of individual whey proteins particularly
α-lactalbumin to enrich infant formulas has significantly
increased after large-scale fractionation procedures utilizing
membrane filtration and ion-exchange techniques became
Table 2. Concentration and Biological Activities of Milk Proteins
Protein Concentration (g/L) Biological Activity
Transport of ions (Ca, PO
, Fe, Zn, Cu)
Precursor of bioactive peptides
Binding of fatty acids
Immunoglobulins 0.7 Immune protection
Antimicrobial, wound healing
Lactoperoxidase 0.03 Antimicrobial, wound healing
Antimicrobial, wound healing
Synergistic effect with lactoferrin
Synergistic effect with immunoglobulins
Adapted from .
1640 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 A. Süha Yalçın
The human immune system has a central role in the de-
fence against bacterial, viral, fungal and parasitic infections
as well as different forms of cancers . Deficiencies in
any aspect of the immune system can predispose an individ-
ual to a greater risk of infection and may enhance severity of
a disease. The immune system employs both specific and
nonspecific immune responses for protection against disease.
Specific immune responses are mediated by T-lymphocytes
and antibodies produced by B-lymphocytes. Non-specific
components of the host defense include physicochemical
barriers such as skin, mucus, lysozyme, complement and
interferons, as well as natural killer cells and phagocytic
Milk contains unique constituents which have been
shown to modulate immune function [24, 25]. Among these
are immunoglobulins, lactoferrin, growth factors and amino
acids necessary to support glutathione production. Pluripo-
tent polypeptides called cytokines that have autocrine and/or
paracrine actions are also present in milk. An active area of
research is the formation of biologically active peptide se-
quences during digestion and their effects on secretion of
enterohormones as well as immune enhancement .
Passive immunity against infection in the intestinal lu-
men is afforded by lysozyme, lactoperoxidase, lactoferrin,
and caseinomacropeptides all of which are constituents of
whey that could also reduce oxidant burdens imposed by
inflammation . Immunoglobulins are also involved in the
passive protection of the young and they partly resist degra-
dation in the intestinal lumen . Studies have also been
performed using immunoglobulins from non-immunized
cows and from cows hyperimmunized against specific
pathogens [29-32]. Colostrum, which is the first milk pro-
duced after birth, is particularly rich in immunoglobulins,
antimicrobial peptides, growth factors as well as other bio-
active molecules . Immunoglobulin concentrations are
greater in whey derived from colostrum. The high immuno-
globulin concentration of colostrum declines during lacta-
Whey products provide active lactoferrin/metal-binding
activities. Lactoferrin acts as a means of both stable iron
delivery and scavenging of free iron by binding iron which
would otherwise catalyze oxidative reactions . Lactofer-
rin has bacteriostatic and bacteriocidal activity against both
Gram-negative and Gram-positive bacteria . Binding to
lipopolysaccharides of Gram-negative bacteria is one of the
antibacterial mode of action of lactoferrin. Fungicidal activ-
ity particularly against Candida species has also been de-
scribed . These activities are not only related to depriva-
tion of iron from the microenvironment but also to binding
of lactoferrin to cell walls causing membrane perturbation
and leakage of intracellular components. Besides a broad
antimicrobial spectrum against bacteria and fungi, lactoferrin
is capable of inhibiting replication of viruses . Lactofer-
rin prevents infection of the host cell, rather than inhibiting
virus replication after the target cell has become infected.
The antiviral activity is in the early phase of the infection
where lactoferrin prevents entry of virus into the host cell,
either by blocking cellular receptors, or by direct binding to
the virus particles. Proteolysis of lactoferrin by pepsin pro-
duces an antimicrobial peptide called lactoferricin. Various
synthetic analogs of lactoferricin are also available. Lactofer-
ricin kills target organisms by membrane perturbation and
acts synergistically with some antimicrobial agents. It inhib-
its a diverse range of microorganisms such as Gram-negative
bacteria, Gram-positive bacteria, yeast, filamentous fungi,
and parasitic protozoa, including some antibiotic-resistant
Oxidative Stress and HIV Infection
A seemingly important feature of whey proteins is the
high concentration of cysteine which is a rate-limiting amino
acid in glutathione synthesis. Glutathione is a major nonpro-
tein sulfhydryl compound of the living cells. It is also a key
molecule for cellular protection against free radicals and
oxidative stress . It has been reported that whey protein
feeding enhances immune responsiveness by increasing tis-
sue glutathione levels [40, 41]. Whey proteins are also good
candidates for dietary suppression of oxidative stress. They
have enhanced host antioxidant defenses and lowered oxi-
dant burden in different experimental models [42-45]. Anti-
oxidant status of the host organism is very important in viral
infections since virulence is linked to passage of non-virulent
forms through hosts with compromised antioxidant status.
HIV infection is characterized by increased oxidative stress
and a systemic deficiency of glutathione [46, 47]. HIV has a
dual response to glutathione. Low cellular glutathione levels
allow the virus to multiply, whereas high glutathione dra-
matically slows viral replication . It was reported that
supplementation with whey proteins increased plasma glu-
tathione levels in glutathione-deficient patients with HIV-
Nutritional studies, reports and trials to identify antican-
cer properties of foods have been extensive . It is gener-
ally agreed that diets that are high in grains, green vegeta-
bles, fresh fruit and fiber, and low in total and saturated fats
are beneficial to health. Relatively less emphasis has been
placed on bovine milk. Epidemiological studies indicate that
humans who consume milk are less likely to develop cancer
of the colon and rectum than those who do not consume milk
. Calcium and vitamin D were identified as protective
against colorectal cancer. The results of a recent study
showed that whey protein concentrate renders tumor cells
more vulnerable to chemotherapy by depleting glutathione
. Whey proteins have also been reported to protect
against chemically induced carcinogenesis in animal models
Stress, Depression and Anxiety
Stress is an important problem of the urban and industri-
alized society. People with increased brain serotonin levels
are able to cope with stress conditions, while a decline in
serotonin activity is associated with depression and anxiety.
Elevated levels of serotonin in the body will result in the
relief of depression, as well as a substantial reduction of pain
sensitivity, anxiety and stress . Recently, investigators
Emerging Therapeutic Potential of Whey Proteins and Peptides Current Pharmaceutical Design, 2006, Vol. 12, No. 13 1641
examined whether α-lactalbumin would increase plasma
tryptophan levels and reduce cortisol concentrations in sub-
jects considered to be vulnerable to stress . They sug-
gested that whey proteins may serve as safe and effective
supplements in the battle against depression and stress.
Adequate flow of saliva is a prerequisite for good oral
health. Hyposalivation leads to many oral problems includ-
ing rapid dental decay, mucosal infections and increased
susceptibility to fungal infections . There have been at-
tempts to enhance or restore salivary antimicrobial capacity
using commercially available oral health care products. The
antimicrobial proteins used in these products are lysozyme,
lactoferrin and lactoperoxidase all of which are present in
whey . On the other hand, demineralization of tooth
enamel, which consists mainly of crystalline calcium phos-
phate embedded in a protein matrix, is initially brought about
by the action of acids which create small cavities. Tooth de-
cay takes place by the action of microflora present in the
plaque. It has been shown that whey proteins exhibit protec-
tive effect against demineralization and act as anticariogenic
Whey contains biologically active molecules capable of
enhancing intestinal health. There are four beneficial areas of
intestinal health modification with whey components: prebi-
otic effects, antimicrobial and antiviral properties, anticancer
properties and influences on immunity . A prebiotic is a
nondigestible food ingredient that beneficially affects the
host by selectively stimulating the growth and/or activity of
one or a limited number of bacteria in the colon. Bifidobacte-
ria and lactobacilli are two groups of bacteria capable of
utilizing prebiotics . They are considered to be beneficial
due to their antimicrobial effects against pathogenic bacteria,
production of B group vitamins, and inhibition of intestinal
precarcinogenic enzymes. Growth promotion of Bifidobacte-
rium species by different whey fractions have been reported
. Glycomacropeptide and lactoferrin have been shown to
support the growth of Bifidobacteria and exhibit prebiotic
Antimicrobial and Bactericidal Activity
Whey contains several unique components with broad
antimicrobial and antibacterial properties. Significant levels
of these compounds have been shown to survive passage
through the stomach and small intestine, and arrive as intact
proteins in the large intestine where they exert their biologi-
cal effects. Immunoglobulins are the best-known of the whey
components that provide antimicrobial action in the intestinal
tract. They predominate in milk-derived sources and may
comprise up to 1 % of the total weight of whey proteins. IgG
has been shown to bind the toxin produced by Clostridium
difficile, thereby reducing the deleterious effects of infection
. Glycomacropeptide also inhibits cholera toxin by
binding to receptors in the intestinal tract .
Antimicrobial peptides represent an important component
of the innate immunity. They can be generated through pro-
teolytic digestion of milk proteins and have the advantage of
being derived from harmless substances. A number of short
peptides with high bactericidal activity have been developed
from the bactericidal domains of α-lactalbumin and β-
lactoglobulin as well as lactoferrin [11, 67, 68].
The role of proteins in the diet as physiologically active
components has been increasingly acknowledged in recent
years [11, 12]. Accordingly, peptides from milk proteins
exhibiting different bioactivities, immunomodulatory action
and mineral utilization properties have been identified (Table
3). Bioactive peptides usually contain 3-20 amino acid resi-
dues per molecule. The biological activity is based on the
Table 3. Bioactive Peptides from Milk Proteins, their Precursors and Bioactivities
Bioactive Peptide Precursor Bioactivity
Casomorphins α- and β-Casein Opioid agonists
α-Lactorphin α-Lactalbumin Opioid agonist
β-Lactoglobulin β-Lactoglobulin Opioid agonist
Lactoferroxins Lactoferrin Opioid antagonists
Casoxins κ-Casein Opioid antagonists
Casokinins α- and β-Casein Antihypertensive
Lactokinins α-Lactalbumin and β-Lactoglobulin ACE-inhibitory
Casoplatelins κ-Casein and Transferrin Antithrombotic
Immunopeptides α- and β-Casein Immunostimulants
Phosphopeptides α- and β-Casein Mineral transport
Lactoferricin Lactoferrin Antimicrobial
Adapted from 
1642 Current Pharmaceutical Design, 2006, Vol. 12, No. 13 A. Süha Yalçın
inherent amino acid composition and sequence. Bioactivities
of several milk proteins are latent, either absent or incom-
plete in the native protein. The active peptide fractions are
released from the native protein/peptide during proteolytic
digestion of the protein. Once the bioactive peptides are lib-
erated, they may act as regulatory compounds with hormone-
like activity. There are a number of methods by which pep-
tides with biological activity can be produced. Pancreatic
enzymes have been utilized for the chemical characterization
and identification of many known bioactive peptides. ACE-
inhibitory peptides are most commonly produced by trypsin
but other enzymes and various combinations of proteinases
as well as enzymes from bacterial and fungal sources have
also been utilized to generate bioactive peptides .
The health promoting powers of whey was discovered
long time ago. Ancient Greeks as well as Hippocrates in 460
B.C., prescribed cheese whey for the assortment of human
ailments. Later in the 17th century during the Italian Renais-
sance sayings about whey flourished in Florence. The im-
portance of whey as a nutrient-rich protein source was rec-
ognized by the scientific community only recently. The
worldwide supply of whey as a co-product of cheese and
casein production has grown rapidly and along with ad-
vanced processing technologies this has expanded the com-
mercial use of whey proteins and their products. Today, it is
accepted that whey products offer a wide range of bioactive
elements capable of promoting health. Many in vitro and in
vivo studies have shown that individual whey proteins have
one or more biological activities.
Whey and its components are involved in different bio-
logical functions including antioxidant activity, anticarcino-
genic effects, immunomodulation, passive immunity, disease
protection, anti-bacterial, anti-microbial and anti-viral ef-
fects, binding of toxins, promotion of cell growth, platelet
binding, anti-inflammatory and anti-hypertensive actions. In
some cases the benefits of whey proteins and peptides have
been demonstrated by clinical trials on humans. In others
there are still gaps in scientific evidence. Nevertheless, the
attention devoted to whey proteins by the industry and the
scientific community strongly indicates that a dynamic
knowledge database will build upon current information and
expand the therapeutic use of whey proteins and peptides.
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