9. Conclusions

structural characteristics of peptides with targeted bioactivity and exploitation of these char-

The term food allergy refers to an immune response directed toward food and affects approximately 8% of children and 1–2% of adults, and its frequency is increasing [35]. Most allergens reacting with IgE antibodies are proteins found in peanuts, soybeans, tree nuts, milk, egg, fish,

European Food Safety Authority (EFSA) encourages the use of in silico tools for initial prediction of potential allergens from food proteins [8]. Although the toxicity and the allergenicity of food products must be assessed also in vitro and in vivo, the in silico tools can be also used to predict the toxicity of peptides [29]. The available bioinformatics-based allergen prediction tools consist of two groups. The first group is based on searches for sequence similarities following the Codex alimentarius guidelines produced by the Food and Agriculture Organization (FAO) and the World Health Organization (WHO), which states that a "protein is potentially allergenic if it either has an identity of over six contiguous amino acids or a minimum of 35% sequence similarity when compared to known allergens" [13]. The second group utilizes databases aiming to identify conserved, allergenicity-related linear motifs [13]. AlgPred (http://www.imtech.res.in/raghava/algpred/) integrates different approaches by means

After ingestion of food, proteins are naturally hydrolyzed in the gastrointestinal digestion. The digestion often produces peptides with low MW and free amino acids, which are transported across the intestine wall [57]. Highly hydrolyzed proteins and peptides with low MW are not generally toxic and are known to be less allergenic than the native proteins and are widely used in the formulation of hypoallergenic infant foods [32]. However, toxic peptides have been identified from plant as well as animal origin, and they can result in acute, physiological effects, and death. Toxic peptides are usually rich in residues like Asn, Cysm His, and Pro, whereas nontoxic peptides contain dominantly residues Ala, Arg, Gln, Ile, Leu, Lys, Met, Phe, Thr, and Val. [53].

Altogether, the in silico assessment of toxicity is not enough, and in vivo studies in animal models should be carried out before human consumption. The in vivo assessment of the toxicity of food products must be carried out following the guidelines proposed by international authorities. Large quantities of scientific evidence and tests need to be carried out on vertebrate models and cell lines, or unicellular microbial species [47]. Multiple peptide toxicity

Intensive research on bioactive peptides being carried out around the world has already led to the introduction of a wide range of commercial products. The bioactive peptides offer an

studies have been carried out in animal models to date [12, 57].

acteristics is a crucial requirement for this approach.

7. Safety aspects of peptides

250 Renin-Angiotensin System - Past, Present and Future

crustaceans, and wheat [53, 70].

to predict the allergenicity of proteins [62].

8. Application

There is no doubt that the hydrolysis of proteins gives rise to diversity of peptides, some of them displaying remarkable functionalities relevant to human health. The research should encourage the industry to invest more in the added-value products with scientific evidence of health benefits. To this end, novel technologies are available to standardize and stabilize the concentrations of active peptides in the products by means of chromatographic, membrane separation techniques, and encapsulation. Important structure-function parameters of peptides are increasing constantly, which can greatly enhance the production and processing of peptides. With improved understanding of the structure-activity relationship, we may be able to design targeted enzyme hydrolysis strategies to release these peptides.

According to Foltz et al. [25], it appears that it is only valid to propose efficacy once the peptide exhibits reasonable proteolytic stability and physiologically relevant absorption, distribution, metabolism, and excretion profiles. In this field, more in-depth topics include the stability of the biological activity of peptides, during processing as well as in vivo in the body before being absorbed and transported to the target site. Greater understanding of the biological fate of peptides and the site of action will allow delivery or an effective dose and formulation of the peptides to ensure that they reach their target sites. Moreover, we need to gain better understanding of the relationship between these in vitro activities and, especially, long-term health benefits in humans and establish appropriate biomarkers of biological efficacy. For example, the extent of the antihypertensive effects has been suggested to depend on the nature of delivery system, dose, study duration, genetic background of the subjects, and stages of hypertension (reviewed in [72]). Furthermore, molecular studies are needed to assess the mechanisms by which bioactive peptides exert their activities in the body. To this end, it may be necessary to employ proteomic and metabolomic methods. By means of these novel nutrigenomic approaches, it is possible and, in future, perhaps essential to investigate the impact of peptides on the expression of genes and hence, endeavor to optimize the nutritional and health effects delivered by peptides.

The safety of all novel peptides intended for food or pharmaceutical uses should be tested in accordance with international and national food safety regulations. In cases of products intended to be marketed in the EU member states, the novel food legislation has to be observed. Other challenges with dietary bioactive peptides are posed by health claims, which in the EU countries are strictly regulated and require science-based documentation before approval by the European Commission. At present, there are worldwide efforts to harmonize these regulations so as to develop fair global food marketing and protect consumers against false or misleading product information.
