Models of antiviral proteins & peptides from milk proteins.
1. Introduction
Milk is thought to be the main source of biologically active compounds for infants, providing antibacterial and antiviral activities, facilitating nutrient absorption, promoting bone growth, enhancing immunological protection and supporting the development of host immune competence. In milk, the main categories of compounds related to antiviral activity through immune stimulation and suppression of host immune inflammation are the casein proteins, whey proteins and their derived peptides [1-3].
Casein proteins, as well as casein fragments, function as antiviral and immune regulatory factors by regulating the innate immune response both through up-regulation to enhance killing of viruses, and down-regulation to reduce detrimental conditions such as sepsis [1, 3-7]. Additionaly, caseins link the innate immune system to the adaptive immune system by activating and/or enhancing B- and T-cell mediated functions. The whey protein lactoferrin, and pepsin derived peptide fragments of this protein (e.g. lactoferricin) have been studied extensively for its antiviral properties [8-10] i.e. its direct interaction with the virus particle, interaction with cellular receptors on the target cells, and lately more complex antiviral mechanisms involving stimulation and regulation of the immune system have been discovered [2, 11-16]. Similarly, peptides tailored on specific protein fragments of casein and α-lactalbumin have also been investigated for their antiviral and immunomodulatory properties. Many of these studies have identified biologically active peptides that can prevent a viral infection, as well as regulate the immune status of the host [1, 2, 17-21]. Currently, some of these peptides are being investigated in clinical trials, like human lactoferrin fragment 1-11 (AM Pharma, Bunnvik, The Netherlands) [22] and LTX-302 (Lytix Biopharma, Tromsø, Norway) [20]. Moreover, another promising class of synthetic peptides with therapeutic potential is a group of innate defence regulator peptides, which exhibit immune protection by enhancing or suppressing the host immune response [23-26]. It is tremendously encouraging that many of these proteins and peptides have pharmaceutical potential within antiviral and anticancer therapy, as vaccine adjuvants, as immunosuppressants for the treatment of autoimmune diseases and in conjunction with organ transplantation, etc. [20, 23-25, 27-29].
Studies have demonstrated that active milk protein and peptide compounds can be extracted from a variety of species including humans, bovine, porcine, mice and camel. The main focus in this paper is the antiviral and immune regulating properties (Table 1) of milk proteins (Table 2) and their peptide derived fragments (Table 3). The vast majority of the discussed studies deal with proteins and peptides of bovine origin, and these will be referenced with their protein names, while proteins and peptides from other origins will be explicitly specified with the species name.
Herpes simplex virus 1 | human and bovine lactoferrin and lactoferricin, lactoperoxidase | Binding to both virus particle and cellular receptors (heparan sulphate) to prevent viral adsorption and entry; Interference with intracellular replication events or synthesis of progeny viral components | [ |
chemically modified milk proteins e.g. serum albumin, α-lactalbumin, β-lactoglobulin | [ | ||
Herpes simplex virus 2 | human and bovine lactoferrin | Binding to virus receptor of non-GAG nature | [ |
-lactoglobuline | Binding to virus particle | [ | |
Hepatitis C virus | lactoferrin | Binding to viral envelope protein E1 and E2 | [ |
Hepatitis B virus | iron- or zinc-saturated lactoferrin | Binding to cellular molecules interfering with viral attachment/entry | [ |
Hepatitis G virus | lactoferrin | Unknown | [ |
Respiratory syncytial virus | lactoferrin, lactoperoxidase | Binding to F1 subunit of RSV F protein to inhibit viral absorption | [ |
Human immunodeficiency virus | human and bovine lactoferrin, lactoperoxidase | Binding to cellular receptor to inhibit viral absorption and replication | [ |
chemically modified milk proteins like serum albumin, α-lactalbumin, β-lactoglobulin | [ | ||
Influenza virus (H3N2, H1N1 and H5N1) | lactoferrin, κ-casein, glycomacropeptide, lactoperoxidase | Binding to hemagglutinin of virus | [ |
modified human serum albumin and β-lactoglobulin, α-lactalbumin, lactoferrin | [ | ||
Human cytomegalovirus | lactoferrin and lactoferricin | Interfere with virus target cells; up-regulation of killer cells; synergistic antiviral effect with cidofovir | [ |
chemically modified milk proteins like serum albumin, α-lactalbumin, β-lactoglobulin | Binding to virus particle | [ | |
Feline herpes virus 1 | human and bovine lactoferrin | Binding to cellular molecules | [ |
Canine herpes virus | human and bovine lactoferrin (apo- and holo-) | Binding to virus particle and cellular receptor on target cell | [ |
Hantavirus | lactoferrin | Binding to cellular molecules; synergistic effect with Ribavirin on inhibiting viral replication | [ |
Vesicular stomatitis virus | lactoferrin | Induction interferon-α/β expression to inhibit viral replication | [ |
Friend virus complex | human lactoferrin | Regulation on the myelopoiesis; synergistic effect with interferon-γ | [ |
Human papillomavirus | human and bovine lactoferrin, human and bovine lactoferricin | Binding to heparan sulphate cell receptor | [ |
Alphavirus heparan sulphate- adapted sindbis virus and semliki forest virus | human lactoferrin, charge-modified human serum albumin | Binding to heparan sulphate cell receptor | [ |
Severe acute respiratory syndrome coronavirus | lactoferrin | Binding to heparan sulphate cell receptor | [ |
Rotavirus | human lactoferrin (apo-/holo-), α-lactalbumin, β-lactoglobulin | Binding to viral particles to prevent both rotavirus haemagglutination and viral binding to receptors on susceptible cells | [ |
human lactadherin | Binding to structural protein of rotavirus and inhibits virus replication | [ | |
high molecular glycoprotein (e.g. mucin) | Inhibitor for viral-cell binding to prevent productive virus infection | [ | |
immune globulin | [ | ||
Poliovirus | lactoferrin, modified bovine β-lactoglobulin | Binding to viral receptor on target cell | [ |
Coxsackie virus | modified bovine β-lactoglobulin | Binding to viral receptor on target cell | [ |
Adenovirus | lactoferrin | Binding to viral protein III and IIIa; competition with virus for common membrane receptors | [ |
Enterovirus (71, echovirus 6) | lactoferrin | Binding to both cellular receptors and the viral surface protein VP1 | [ |
Felin calicivirus | lactoferrin | Binding to cell receptor | [ |
Echovirus | lactoferrin, lactoperoxidase | Binding to cell receptor and viral structural proteins | [ |
2. Protein composition of milk and their antiviral activity
There are in general two groups of proteins found in milk, casein and whey. The casein family accounts for approximately 80% of the protein mass and includes several types of casein, e.g. αs1, αs2, β and κ, which form micelle complexes in the water phase of milk. The whey proteins account for the remaining 20%, and include β-lactoglobulin (not present in human milk), α-lactalbumin, serum albumin, immunoglobulins, lactoferrin, transferring, and many minor proteins. Most of the whey proteins have been demonstrated to effectively prevent viral infection. For example, milk derived proteins including α-lactalbumin, β-lactoglobulin, apo-lactoferrin (iron free), and homo-lactoferrin (Fe3+ carrying), were able to inhibit rotavirus attachment to cellular receptors by binding to the viral particle [30]. Among these proteins, apo-lactoferrin was proven to be the most active. Studies also showed that immunoglobulins of raw milk from non-immunized cows and camels, as well as from a commercially available bovine macromolecular whey protein fraction, have specific antibodies against human rotavirus, which are capable of inhibiting replication of rotaviruses in tissue culture and protect mice from infection in a murine model of rotavirus infection [31-33]. Lactoperoxidase, a haem-containing glycoprotein of the mammalian peroxidase family, is an important enzyme in the whey fraction of milk. In combination with its physiological substrates hydrogen peroxide and thiocyanate, lactoperoxidase manifests a wide spectrum of virucidal activities against human immunodeficiency virus, herpes simplex virus 1, respiratory syncytial virus and echovirus [34, 35]. Oral administration of lactoperoxidase also attenuate pneumonia in influenza virus infected mice through suppression of infiltration of the inflammatory cells in the lungs [36]. Furthermore, the 46kD glycoprotein termed lactadherin, also known as milk fat globule-EGF factor 8 protein, inhibited rotavirus binding to cellular receptors (acetylneuraminic acid and/or integrin) on target and/or specifically interacting with viral structural glycoprotein VP4 of rotavirus, blocking host-pathogen interaction [37-40].
Lactoferrin, first isolated in 1960 from both human [41, 42] and bovine milk [43], has been demonstrated to exhibit antiviral activity against many viruses [8, 10-16, 18, 19, 40, 44-74] (Table 2). Most studies indicate that lactoferrin and its derived peptides are likely to interfere in the virus host cell interaction (Figure 1). For example it has been demonstrated that lactoferrin is able to bind both viral receptor and the viral surface protein VP1 on enterovirus (enterovirus 71 and echovirus 6), thus interfering with viral entry [51, 66, 67, 75, 76]. Similarly, both apo- and holo-lactoferrin has been demonstrated to interact both with canine herpes virus and surface receptors on the Madin-Darby canine kidney cells, thus inhibiting canine herpes virus infection [74]. With regard to the anti-herpes simplex virus 1 ability of lactoferrin, both bovine and human lactoferrin and lactoferricin have demonstrated the ability to block viral entry and also inhibit viral cell-to-cell spread in a dose dependent manner [55, 77-79], through interaction with negatively charged glycosaminoglycans like heparan sulphate on the cell surface [55, 80-83] and elements of the viral particle [55]. Differently from herpes simplex virus 1, Marchetti
Many of the traditional entry blocking effects observed by lactoferrin involve electrostatic interaction with anionic heparan sulphate molecules on the host cell surface [82]. The ability to interact with anionic heparan sulphate is maybe not that surprising, when evaluating the three dimensional structural composition of lactoferrin, demonstrating a rather striking cationic patch on the N-terminal lobe of the molecule [84] (Figure 1). Similarly, other highly cationic peptides have also been demonstrated to effectively interfere with herpes simplex virus attachment and entry [80, 85].
Conversely, several other milk proteins i.e. β-lactoglobulin [86], α-lactalbumin [87] are described with anionic patches on their surfaces, while the casein homologues like αs2-casein [88] have both specific anionic and cationic patches on the surface (Figure 1). Thus, charge modification of milk proteins may increase their ability to interfere with virus host cell interactions. 3-hydroxyphthalic anhydride modification of human and bovine serum albumin, and bovine β-lactoglobulin, increased the proteins negative charges in addition to their ability to prevent interaction between human immunodeficiency virus 1 envelope glycoprotein gp120 and the CD4 host cell receptor, by direct interaction and blocking of the CD4 receptor [89, 90]. Similar effects have also been observed for 3-hydroxyphthalic anhydride modified α-lactalbumin and αs2-casein, as well as for maleylated- and succinylated-human serum albumin, indicating that human immunodeficiency virus inhibition was a general property of negatively charged polypeptides [9, 91, 92]. Among the inhibitory proteins, 3-hydroxyphthalic anhydride β-lactoglobulin also demonstrated a broad spectrum activity affecting herpes simplex virus 1 and 2 in addition to human cytomegalovirus by binding to the virus particles, inhibiting particularly the binding of monoclonal antibodies towards glycoprotein E and glycoprotein C [93]. Comparative results have been shown for anionic-modified human serum albumin and β-lactoglobulin which prevents influenza virus membrane fusion with the host cell membrane, a process mediated by the viral glycoprotein hemagglutinin [94]. Interestingly, this anti-influenza effect has not been observed for other milk proteins carrying negative charges, like succinylated bovine serum albumin, lactalbumin, lactoferrin, lysozyme and transferrin [94]. It is said that inhibition of viral fusion demonstrates a certain degree of specificity for negative charged proteins. However, addition of net negative charges to lactoferrin by acylation with either succinic- or acetic anhydride abolished its anti-poliovirus and anti-feline calicivirus activity, which may be attributed to the obliterate binding of acylated lactoferrin to the surfaces of susceptible cells [95]. Also, when negatively charged groups were added to lactoferrin by succinylation, the antiviral effect on human immunodeficiency virus 1 was increased, but the antiviral potency against human cytomegalovirus was mostly decreased [96], illustrating the proteins different modes of action. Similar results were also obtained by Florisa
Source | Protein | % of whey protein | % of casein | Molecular size (kDa) | Nature | PDB code |
Whey | β-lactoglobulin | 50-55 | NA | ~18.4 | Apolipoprotein | 1DV9 |
α-lactalbumin | 20-25 | NA | ~14.1 | Albumin | 1A4V | |
Immunoglobulins | 10-15 | NA | ~150 | Glycoprotein | ﹉ | |
Lactoferrin | 1-2 | NA | ~80 | Glycoprotein | 1BLF | |
Lactoperoxidase | 0.5 | NA | ~70 | Glycoprotein | 3GC1 | |
Serum albumin | 5-10 | NA | ~66 | Albumin | ||
Glycomacropeptide | 10-15 | NA | --- | Phosphoprotein | ||
Casein | αs1-casein | NA | 40-50 | ~23 | Phosphoprotein | |
αs2-casein | NA | 10-15 | ~23 | Phosphoprotein | 1NA7 | |
β-casein | NA | 30-35 | ~24 | Phosphoprotein | ||
κ-casein | NA | 10-15 | ~19 | Phosphoprotein | ||
γ-casein | NA | 5-10 | ~75-100 | Phosphoprotein | 2CHL |
The strong antiviral activity of poly-cationic compounds is generally explained by the compounds ability to interact with anionic heparan sulphate on the host cell surface, which works as a broad spectrum attachment receptor for several viruses [97, 98]. Thus, it is not surprising that methylated or ethylated α-lactalbumin and β-lactoglobulin demonstrate antiviral activity against the bacteriophage M13 through the inhibition of the phage DNA replication, as well as against herpes simplex virus 1 replication, with increasing activity proportional to the extent of esterification or increased basicity of the modified proteins [99, 100]. The net positive charge-modified human serum albumin had a similar antiviral effect as lactoferrin, against heparan sulphate adapted sindbis virus and semliki forest virus, by blocking the virus receptor on the cell surface, indicating that the antiviral activity of lactoferrin mainly is related to its net positive charge [73]. Methylated α-lactalbumin, β-lactoglobulin and lactoferrin also demonstrate enhanced antiviral activity against human influenza virus A subtype H3N2 and subtype H1N1 [101, 102], and lethal avian influenza A (H5N1) [103]. This effect is most likely linked to the disruption of the electrostatic interactions within hemagglutinin, by the esterified whey proteins, thus affecting the proteins stability and capacity to trigger envelope fusion with the host cell. Furthermore, methylation of β-lactoglobulin does also enhance the proteins antiviral activity against coxsackie virus and poliovirus type 1 in a dose dependent manner [104]. This illustrates that chemically modified whey proteins with added negative or positive charges can exert increased antiviral effect against a diverse group of viruses, through different antiviral mechanisms. The virucidal activity of the modified milk proteins, with additional negative charges, may attribute to a stronger interaction of these proteins with the viral envelope proteins. Esterification of whey proteins with methanol or ethanol would increase their cationic charge, thus increasing their affinity for negatively charged macromolecules such as host cell receptors and viral DNA or RNA, thus inhibiting viral attachment to cellular membranes or inhibiting viral replication and transcription, respectively. The structural differences between enveloped and non-enveloped viruses in addition to the unique protein composition in milk from different species preclude a generalized conclusion of the milk proteins potential. Thus, further studies should be carried out to identify the underlying molecular interactions involved, and the true therapeutic potential of these milk derived molecules.
3. Traditional antiviral mechanisms of milk-derived proteins
The life cycle of a virus comprises several phases such as binding to the host cell surface, entry or fusion, replication of the viral genome, viral protein synthesis, virus progeny assembly and release. All these steps may be targeted by antiviral agents or milk derived proteins.
Many of the antiviral milk proteins can bind to structural proteins of the virion in order to prevent binding of the virus to the target cell and subsequently inhibit entry of the viral genome into the host cell. Human lactoferrin (apo- or Fe3+), α-lactalbumin, β-lactoglobulin, human lactadherin, mucin, and immunoglobulin from milk could prevent rotavirus infection through the binding to structural viral protein VP4 [30, 37, 38, 40, 107, 108]. Also, the antiviral activity of lactoferrin against adenovirus has been attributed to the interaction of the milk protein with viral capsid proteins [60, 61, 69].
Furthermore, Ikeda
Hemagglutinin is an antigenic glycoprotein found on the surface of influenza viruses. The glycoprotein has two main functions; recognition of target cells through the binding of sialic acid-containing receptors and facilitating entry of the viral genome into the target cells by initiating fusion of host endosomal membrane with the viral membrane. Thus, targeting the hemagglutination activity of hemaglutinin could be a robust mechanism in fighting influenza virus infections. Influenza hemaglutinin has also successfully been targeted by both human and bovine lactoferrin (apo- and holo-), as well as κ-casein glycomacropeptide, reduce viral hemagglutination [30, 53]. Moreover, the addition of methylated β-lactoglobulin in the medium of Madin-Darby canine kidney cell lines infected with influenza virus H1N1 reduced hemagglutination in a concentration-dependent manner [101].
Although it has been identified that a metallopeptidase, angiotensin-converting enzyme 2, is a functional receptor for severe acute respiratory syndrome coronavirus infection [115], other reports have demonstrated that DC-SIGN, L-SIGN (also called CD209L, specific for liver/lymph node) [116-119], and heparan sulphate [120] also are involved in the virus pathogenesis. Thus, there are reasons to believe that lactoferrin could prevent severe acute respiratory syndrome coronavirus spread in the host through the same mechanism as described for human immunodeficiency virus, by interacting with DC-SIGN or heparan sulphate receptors. Recently, Lang
Human papillomavirus can also use heparan sulphate on the target cell surface as a receptor. Thus, by incubating HaCaT cells and papillomavirus 16 virus like particles with human and bovine lactoferrin Drobni
In a classical pre-incubation study on Vero E6 cells, it was demonstrated that lactoferrin had enhanced antiviral activity against hantavirus infection when added prior to infection. However, this boost in activity could be removed if the cells were subsequently washed with phosphate buffered saline prior to infection [72, 122]. These results might be explained by the weak interaction between lactoferrin and other cellular molecules rather than heparan sulphate, as the interaction between lactoferrin and heparan sulphate should withstand phosphate buffered saline washing [80]. Further research should be developed to identify whether β3 integrin and/or β1 integrin molecules are binding to lactoferrin [123-125].
Similarly, using indirect immunofluorescence, McCann
4. Modulation of innate immune responses - A novel antiviral strategy
The immune system consists of the innate and the adaptive branch, which exerts its functions through recognition of foreign pathogen resulting in a series of responses to eliminate the infectious material. Both innate leukocytes (including macrophages, dendritic cells, and natural killer cells) and adaptive immune cells (B-cells and T-cells) are involved in host immune protection and bridging these two pathways is a variety of traditional signal molecules (cytokines and chemokines). Recently it has also been documented that natural occurring host defence peptides (and proteins) are involved in the orchestration of a well balanced and effective immune response [127-129]. Lactoferrin is one such host defence protein, and it has been demonstrated that lactoferrin can increase the cytotoxic functions of natural killer cells and lymphokine-actived killer cells especially in infants, which normally have low activity in these cell populations [130]. Lactoferrin can also enhance the mobility of polymorphonuclear leucocytes and increase the production of superoxide [131], activate macrophages and stimulate the release of both pro- and anti-inflammatory cytokines, i.e. interleukin-1,-6,-8,-18, interferon-γ and tumor necrosis factor-α [132]. The antiviral effect of lactoferrin on cytomegalovirus in a murine infection model has been demonstrated to be a result of augmentation of natural killer cell activity rather than of the cytolytic T-lymphocytes [14]. Similarly, human lactoferrin has also been proven to have an effect on natural killer cell cytotoxicity against haematopoietic and epithelial tumor cells [133].
Furthermore, the antiviral activity of lactoferrin against vesicular stomatitis virus has been related to its capacity of up-regulating the accumulation of interferon-β in peritoneal macrophages from mice [11]. Another experiment with interperitoneal administration of lactoferrin to CBA mice demonstrated enhanced production of tumor necrosis factor-α and interleukin-12. Similar results were also reported after
With regard to modulation of the adaptive immune system, lactoferrin could exert higher growth stimulatory activity on lymphocytes than transferrin [139], induce phenotypic changes of immature B- and T-cells from newborn or chromosome X-linked immunodeficient mice, as well as enable B-cells to present antigen to an antigen-specific T-helper type 2 cell line [140, 141]. Immature B-cells cultured with lactoferrin will also increase their ability to promote antigen-specific T-cell proliferation, indirectly indicating enhanced B-cell antigen presentation [140].
In summary, the effects of lactoferrin on the activation, maturation, migration and antigen presentation of the innate and adaptive immune cells, suggest that lactoferrin have the potential to associate the cellular functions and responses of the innate and adaptive immune cells, respectively. The modulating effects of lactoferrin on cytokine levels, especially of interleukin-12 and interleukin-18 illuminates the milk proteins role in connecting the innate and adaptive immune response.
5. Milk derived peptides as immune modulators
There is a great quantity of milk proteins and peptides other than lactoferrin that can lead to immune regulation, involving in both up- and down-regulation of the immune system. Peptides from casein [4, 6, 142], β-lactoglobulin [143, 144], and α-lactalbumin [7] also enhance and/or suppress immune cell function (Table 3).
αs1-casein | 23-27 | FFVAP | α-casokinin-5 | ACE-inhibition | [ |
28-34 | FPEVFGK | α-casokinin-7 | ACE-inhibition | [ | |
23-34 | FFVAP FPEVFGK | ACE-inhibition | [ | ||
104-109 | YKVPQL | ACE-inhibition | [ | ||
158-162 | YVPFP | αs1-casomorphin | Opioid agonist, immunomodulation | [ | |
169-193 | LGTQYTDAPSFSDIPNPIGSENSEK | ACE-inhibition | [ | ||
194-199 | TTMPLW | α-casokinin-6 | ACE-inhibition, immunostimulatory activity | [ | |
201-212 | IGSENSEKTTMP | ACE-inhibition | [ | ||
αs2-casein | 94-103 | QKALNEINQF | ACE-inhibition | [ | |
163-176 | TKKTKLTEEEKNRL | ACE-inhibition | [ | ||
β-casein | 1-25 | RELEELNVPGEIVES (P)LS(P)S(P)S(P)EESITR | casein phosphopeptide | Immunostimulatory activity | [ |
54-59 | VEPIPY | Immunostimulatory activity | [ | ||
60-66 | YPFPGPI | β- casomorphin-7 | ACE-inhibition, immunomodulation activity | [ | |
63-68 | PGPIPN | Immunomodulation | [ | ||
60-70 | YPFPGPIPN | β- casomorphin-11 | Immunostimulatory activity, opioid and ACE-inhibitory activities | [ | |
73-89 | NIPPLTQTPVVVPPFIQ | ACE-inhibition | [ | ||
114-118 | YPVEP | β-casochemotide-1 | Promote innate host immune response | [ | |
124-133 | MPFPKYPVEP | ACE-inhibition | [ | ||
169-175 | KVLPVPQ | ACE-inhibition | [ | ||
177-183 | AVPYPQR | β-casokinin-7 | ACE-inhibition | [ | |
191-193 | LLY | Immunomodulation activity | [ | ||
193-202 | YQQPVLGPVR | β-casokinin-10 | ACE-inhibition, immunostimulatory activity | [ | |
210-221 | EPVLGPVRGPFP | ACE-inhibition | [ | ||
κ-casein | 108-110 | IPP | ACE-inhibition | [ | |
106-116 | MAIPPKKNQDK | casoplatelin | Antithrombotic activity | [ | |
YIPIQYVLSR | Casoxin C | Opioid agonist | [ | ||
YPSY | Casoxin 4 | Opioid agonist | [ | ||
α-lactalbumin | 18-20 | YGG | Immunomodulation | [ | |
50-53 | YGLF | α-lactorphin | ACE-inhibition | [ | |
99-108 | LDDDLTDDI | ACE-inhibition | [ | ||
104-108 | LTDDI | ACE-inhibition | [ | ||
β-lactoglobulin | 22-25 | TMKG | ACE-inhibition | [ | |
32-40 | AGTWYSLAM | ACE-inhibition | [ | ||
94-100 | IPAVFKI | ACE-inhibition | [ | ||
106-111 | NKVLVL | ACE-inhibition | [ | ||
102-105 | YLLF | β-lactorphin | ACE-inhibition | [ | |
142-148 | ALPMHIR | ACE-inhibition | [ | ||
Bovine serum albumin | 399-404 | YGFQNA | serorphin | Opioid | [ |
208-216 | ALKAWSVAR | albutensin A | ACE-inhibition | [ | |
Bovine lactoferrin | 17-41 | FKCRRWQWRMKKLGAPSITCVRRAF | lactoferricin | Anti-herpes simplex virus activity, ACE-inhibition, immunomodulation activity | [ |
17-26 | FKCRRWQWRW | immunomodulation activity | [ | ||
Human lactoferrin | 1-49 | GRRRRSVQWCAVSQPEATKCFQWQR NMRKVRGPPVSCIKRDSPIQCI | lactoferricin | Anti-herpes simplex virus activity | [ |
1-32 | GRRRRSVQWCAVSQPEATKCFQWQR NMRKVRGP | LF-33 (human) | Anti-human immunodeficiency virus activity | [ | |
222-230; 264-268 | ADRDQYELL; EDLIWK | Inhibit herpes simplex virus 1 infection | [ | ||
268-284 | KWNLLRQAQEKFGKDKS | Lactoferrampin | Immunomodulation activity | [ | |
318-323 | YLGSGY | Lactoferroxin A | Opioid agonist | [ | |
536-540 | RYYGY | Lactoferroxin B | Opioid agonist | [ | |
673-679 | KYLGPQY | Lactoferroxin C | Opioid agonist | [ |
Immunomodulating casein peptides have been found to stimulate the proliferation of human lymphocytes and the phagocytic activities of macrophages [4]. Casein phosphopeptides from fermented milk products, such as plain yogurts and cheeses, has shown beneficial effects on the immune system including the mitogenic effect and IgA enhancing effect in mouse spleen cell cultures [3]. According to the results of other studies, human β-casein fraction 54-59 has demonstrated to enhance the phagocytic activity of macrophages both in mice and humans and increase resistance against certain bacteria in mice [6, 149].
Chemotactic factors in the tissue do also play an essential role in host defence against microbial infection by inducing leukocyte infiltration. A pentapeptide (β-casochemotide-1) with amino acid sequence (YPVEP) matching an actinase E digest peptide from bovine β-casein (corresponding to fraction 114-118), has been tested and demonstrated to both chemoattract and activate, human and mouse monocytes and macrophages by using a unique G-protein coupled receptors [142].
In addition, Colostrinin, also known as PRP, is a naturally occurring mixture of proline-rich polypeptides derived from colostrums and it can stimulate the immune response in animal and
The opioid system plays a major role in immune modulation, both through classical opioid receptor, but also through other mechanisems. For example, opioid peptides have been demonstrated to inhibit phagocytosis [157], decrease natural killer cell number and activity and decrease cell-mediated hypersensitivity [158]. Also, αs1-casomorphin, an opioid agonist, can modulate antibody and cytokine secretion by multiple myeloma cells in a cell line-dependent and opioid receptor-independent manner, but it was shown to decrease the antibody secretion by normal B-lymphocytes and the proliferation rate of multiple myeloma cells through opioid receptor activation [159]. In other words, there might be two different opioid mechanisms, mediated by parallel signalling pathways, i.e. one early non-opioid receptor related effect modulating the constitutive secretion of immunoglobulin and cytokine, as well as a second long lasting receptor-mediated action of cell growth. Thus, opioids might be employed in controlling the humoral immunity.
Furthermore, the rennin-angiotensin-aldosterone system is not only a major regulator of blood pressure; it also plays a key role in autoimmunity. The angiotensin peptide (AII), is one component of the rennin-angiotensin-aldosterone system, and has direct activity on T-cell function, including activation, expression level of tissue-homing markers and production of tumor necrosis factor-α [160]. Inhibitors of angiotensin-converting enzyme will dampen the proteolytic process of the larger angiotensin peptides (AI) to the active AII. Thus, inhibition of T-cell angiotensin-converting enzyme blocks production of tumor necrosis factor-α, which modulates the proliferation of human immunodeficiency virus [161] and regulates the helper activity in B-cell activation [162]. This will also suppress the auto-reactive T-helper 1 and T-helper 17 cells and promotes antigen-specific CD4+FoxP3+ regulatory T-cells through inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway [163]. Moreover, angiotensin-converting enzyme inhibitors play a pivotal role in immune defence by decreasing the degradation of bradykinin and enkephalin [4, 164].
A variety of angiotensin-converting enzyme inhibitory peptides have been found in the hydrolysates of milk using different enzymes; the bovine αs1-casein (fragment) f24-47, f104-109, f169-193, f194-199 and f201-212, αs2- casein f94-103 and f163-176, β-casein f60-66, f60-70, f169-175, f177-183 and f193-202, α-lactalbumin f18-20 and f50-53; β-lactoglobulin f102-105 and f142-148, bovine serum albumin f208-216, lactoferrin f17-41 (Table 3). Among all these angiotensin-converting enzyme inhibitors, it should be emphasised that peptides αs1-casein f194-199, β-casein f60-66 and f193-202 have shown to have both angiotensin-converting enzyme inhibitory activities and immune stimulatory effect.
Moreover, recombinant human αs1-casein expressed in
6. Synergy between milk proteins and conventional antiviral drugs
A combination of human lactoferrin with recombinant murine interferon-γ resulted in synergistic suppressive effects on disease progression in friend virus complex infected mice [56]. The experiment concluded that natural killer cell activity decreased by friend virus complex, and that the cellular activity returned to normal levels and survival rates increased upon treatment with lactoferrin and interferon-γ. Another study also supporting immune cell regulation by lactoferrin was performed by Spadaro
Also, combined pre-infection administration of lactoferrin with post-infection administration of Ribavirin on Vero E6 cells could completely inhibit focus formation during hantavirus infection (similar to the traditional plaque formation). This combination therapy also demonstrated significantly increased survival rates in an
Although it is known that lactoferrin has been used to inhibit initial viral infection by interfering with viral attachment and/or entry, the mode of antiviral activity against lots of viruses needs to be clarified in the future, e.g. the infection with hepatitis G virus in human MT-2C T-cells was prevented by bovine lactoferrin with no clear mechanism [63]. With regard to friend virus complex infection, most researchers have confirmed that human lactoferrin has anti-friend virus complex activity in a mouse leukemia model [57, 64], but have no direct effect on friend virus complex infection
7. Commercial potential of milk derived proteins and peptides.
Additionally, synthetic peptides derivatives tailored on natural milk proteins or fragments there of, may be another powerful way for design of immune regulating pharmaceutical candidates. For example, synthetic peptides tailored from milk proteins have been shown to enhance proliferation of human peripheral blood lymphocytes. In particular, two fragments (YG and YGG), of bovine α-lactalbumin (fraction 18-19 and 18-20) can significantly stimulate the lymphocyte proliferation, while β-casomorphin-7 and β-casokinin-10, corresponding to fragments 60-66 and 193-202 of bovine β-casein, respectively, suppresses lymphocyte proliferation at low concentrations while enhanced proliferation at high concentrations [1] (Table 3).
Recent studies have shown that synthetic innate defence regulator peptides offer protection by enhancing innate immune defenses of the host while suppressing potentially harmful excessive inflammatory response triggered by the invading pathogen. For example, innate defence regulator peptide 1 was chemotactic for T-helper cells type 1 [23], monocytes [27] and neutrophil response [28], acting in a mitogen-activated protein kinase-dependent manner, while reducing pro-inflammatory cytokine responses. Another peptide, innate defence regulator 1002, induces chemokines in human peripheral blood mononuclear cells [24] which prevents the production of interleukin-1β-induced matrix metalloproteinase 3 and monocyte chemotactic protein-1 and selectively suppresses the inflammatory response [25].
With the aid of computational molecular modeling technologies, theoretical prediction of immune regulatory peptides has become available and practical. For example, RDP58, a novel d-amino acid decapeptide (r-(nle)3-r-(nle)3-gy-CONH2), which was developed by computer-aided rational based design on human leukocyte antigen-derived peptides [177], has been discovered to suppress the T-helper 1 cytokine profile, decrease production of inflammatory cytokines including tumor necrosis factor-α, interferon-γ, interleukin-2 and interleukin-12 in both cell lines and animal models [26, 178, 179]. Several clinical trials on human including phase I safety in normal volunteers, phase II mild-moderate active ulcerative colitis, phase II moderate active ulcerative colitis and phase IICrohn’s disease had been completed (Genzyme Corporation; Sanofi, Bridgewater, NJ). Moreover, quantitative structure-activity relationship analysis has been done for peptide design and optimization in developing novel antimicrobial drugs [180-183], and the numerical improvements of quantitative structure-activity relationship studies has been exemplified recently [184], though there are limitations to the predictive ability of the models [185, 186] this technology clearly accelerates lead peptide discovery.
Suppression of immunological functions by milk derived proteins is thought to be important in the ontogeny of the neonatal gastrointestinal immune system, specifically by ensuring a state of tolerance with respect to food proteins. Kulkarni and Karlsson has demonstrated the essential role of milk-derived immunosuppressive factors (i.e. growth factor-β) during early development, and that neonatal mice deficient in transforming growth factor-β remain viable only as long as they receive maternal milk containing this same growth factor [187].
Also, it is envisaged that most of the potential immunosuppressive activity of milk-derived peptides would be effective on chronic inflammatory diseases and organ transplant patients by decreasing allergy, autoimmunity, and organ rejection. For example, lactoferrin could enhance the production of anti-inflammatory factors, like interleukin-11, not only in a hepatitis mouse model, but also in human intestinal myofibroblasts [188]. Additionally, hydrolysis of caseins with L. casei GG-derived enzymes has generated molecules with suppressive effects on lymphocyte proliferation and benefited the intestinal bacteria in the down-regulation of hypersensitivity reactions to ingested proteins in patients with food allergy [189]. Furthermore, two synthesized analogs of the hexapeptide of human β-casein (fraction 54-59) with modification at the N-terminal region not only showed inhibition in alloantigen inducing lymphocyte proliferation and production of interferon-γ in a SRBC mice model, but also demonstrated increased production of interleukin-4 and improved the skin graft survival. Thus, these peptides might serve as good templates for development of safe and effective immunosuppressant drugs [17]. Similarly, two other synthetic β-casein peptides HLPLP and WSVPQPK, have demonstrated potent antioxidant activity and inhibitory activity of angiotensin-converting enzyme [190]. Accordingly, proteins and peptides from milk could potentially be used in production of immune stimulating- and immunosuppressant agents for both prophylaxis and treatment of infectious diseases and immune related illnesses.
Most of the proteins and peptides with antiviral potential has also demonstrated synergy with conventional antiviral drugs, reducing the dose of the antiviral drugs, and limiting the development of drug-resistant viruses on account of the selective targeting of the host rather than infectious pathogens. At the present time, many peptides with immune regulating effects have been approved for clinical use against virus infection, such as Zadaxin, IM862, SCV-07 and so on [193]. Similarly, two peptide inhibitors of interleukin-10 may be applied to increase anti-hepatitis C virus immune response by restoring the immune stimulatory capabilities of dendritic cells, which have been suppressed by high levels of interleukin-10 [194]. Moreover, candidacidal activities of a synthetic peptide from human lactoferrin fraction 1-11 and 21-31 have been investigated for killing of multidrug-resistant pathogens [195-199]. Present research results, such as phase I safety and tolerability trials of human lactoferrin by AM Pharma [22], indicate that human lactoferrin 1-11 acts by selectively stimulating the innate immune system [200]. Thus, human lactoferrin 1-11 is more likely to be an interesting candidate for further exploration in various clinical tests, such as coating for dental or bone implants, in biosensing applications or in radiopharmaceutical therapy [199].
An innate defence regulator peptide, HH2, has shown synergy with oligonucleotides containing CpG motifs, when used as an immunoadjuvant to enhance the immune response through stimulation of T-helper 1 and T-helper 2 responses in newborn piglets which were vaccinated with a pseudorabies attenuated virus vaccine [29]. Recently, Brown
In addition, the synthetic peptide, P60 (RDFQSFRKMWPFFAM) [219], has demonstrated potential of inhibiting the immunosuppressive activity of murine and human derived regulatory T-cells and enhances the effector T-cell stimulation
8. Conclusion
Most of the milk proteins and peptides that have been identified with antiviral properties are broad spectrum components targeting general features and mechanismes involved in a viral infection cycle. Hence, many of these milk proteins do also demonstrate synergy with conventional antiviral drugs. Recently, the diverse immunomodulatory activities of milk proteins/peptides have illustrated these molecules interesting potential as antiviral therapeutics, though the precise mechansiems of immune regulation needs to be thoroughly described. Although the synthetic peptides usually are shorter than natural proteins, the antiviral immune regulating properties of many of these synthetic derivatives appear to be similar as for the entire proteins. Thus we would argue that milk proteins and peptides, have great potential to serve as templates for design of more potent antiviral drugs. With proper scientific effort these molecules may have great therapeutic potential as supplements for current antiviral and anticancer therapy, as novel vaccine adjuvants for both human and far animals, and as immunosuppressants for autoimmune diseases and allergy treatment.
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