Marine Bioactive Peptides: Anti-Photoaging Mechanisms and Potential Skin Protective Effects.

Skin photoaging, resulting from prolonged exposure to ultraviolet radiation, is a form of exogenous aging that not only impacts the aesthetic aspect of the skin but also exhibits a strong correlation with the onset of skin cancer. Nonetheless, the safety profile of non-natural anti-photoaging medications and the underlying physiological alterations during the process of photoaging remain inadequately elucidated. Consequently, there exists a pressing necessity to devise more secure interventions involving anti-photoaging drugs. Multiple studies have demonstrated the noteworthy significance of marine biomolecules in addressing safety concerns related to anti-photoaging and safeguarding the skin. Notably, bioactive peptides have gained considerable attention in anti-photoaging research due to their capacity to mitigate the physiological alterations associated with photoaging, including oxidative stress; inflammatory response; the abnormal expression of matrix metalloproteinase, hyaluronidase, and elastase; and excessive melanin synthesis. This review provides a systematic description of the research progress on the anti-photoaging and skin protection mechanism of marine bioactive peptides. The focus is on the utilization of marine bioactive peptides as anti-photoaging agents, aiming to offer theoretical references for the development of novel anti-photoaging drugs and methodologies. Additionally, the future prospects of anti-aging drugs are discussed, providing an initial reference for further research in this field.

Chemo-Enzymatic Derivatization of Glycerol-Based Oligomers: Structural Elucidation and Potential Applications.

Switching from oil-based to bio-based feedstocks to ensure the green transition to a sustainable and circular future is one of the most pressing challenges faced by many industries worldwide. For the cosmetics and personal and house care industries there is a strong drive to accelerate this transition from the customers that starts favoring the purchase of naturally derived and bio-degradable products over the traditionally available products. In this work we developed a series of fully biobased macromolecules constituted of a glycerol-based oligoester backbone. Based on the subsequent derivatization with fatty acids or peptides, the resulting products may find application as emulsifiers, wetting agents, and potential vectors for the delivery of bioactive peptides. All steps of the resulting macromolecules were conducted following the green chemistry principles with no toxic or environmentally damaging compounds that were used in the overall production process.

Identification of DPP-IV inhibitory peptides derived from buffalo colostrum: Mining through bioinformatics, in silico and in vitro approaches.

Bioactive peptides derived from foods provide physiological health benefits beyond nutrition. This study focused on profiling small peptide inhibitors against two key serine proteases, dipeptidyl peptidase-IV (DPP-IV) and prolyl oligopeptidase (POP). DPP-IV is a well-known protein involved in diverse pathways regulating inflammation, renal, cardiovascular physiology, and glucose homeostasis. POP is yet another key target protein for neurodegenerative disorders. The study evaluated peptide libraries of buffalo colostrum whey and fat globule membrane proteins derived from pepsin and pepsin-pancreatin digestion through in silico web tools and structure-based analysis by molecular docking and binding free-energy estimation, followed by in vitro assay for DPP-IV inhibition for the lead peptides. The bioinformatic study indicated 49 peptides presented motifs with DPP-IV inhibition while 5 peptides with sequences for POP inhibition. In the molecular docking interactions study, 22 peptides interacted with active site residues of DPP-IV and 3 peptides with that of POP. The synthesized peptides, SFVSEVPEL and LTFQHNF inhibited DPP-IV in vitro with an IC50 of 193.5 µM and 1.782 mM, respectively. The study revealed the key residues for inhibition of DPP-IV and POP thus affirming the DPP-IV inhibitory potential of milk-derived peptides.

Identifying multi-functional bioactive peptide functions using multi-label deep learning.

The bioactive peptide has wide functions, such as lowering blood glucose levels and reducing inflammation. Meanwhile, computational methods such as machine learning are becoming more and more important for peptide functions prediction. Most of the previous studies concentrate on the single-functional bioactive peptides prediction. However, the number of multi-functional peptides is on the increase; therefore, novel computational methods are needed. In this study, we develop a method MLBP (Multi-Label deep learning approach for determining the multi-functionalities of Bioactive Peptides), which can predict multiple functions including anti-cancer, anti-diabetic, anti-hypertensive, anti-inflammatory and anti-microbial simultaneously. MLBP model takes the peptide sequence vector as input to replace the biological and physiochemical features used in other peptides predictors. Using the embedding layer, the dense continuous feature vector is learnt from the sequence vector. Then, we extract convolution features from the feature vector through the convolutional neural network layer and combine with the bidirectional gated recurrent unit layer to improve the prediction performance. The 5-fold cross-validation experiments are conducted on the training dataset, and the results show that Accuracy and Absolute true are 0.695 and 0.685, respectively. On the test dataset, Accuracy and Absolute true of MLBP are 0.709 and 0.697, with 5.0 and 4.7% higher than those of the suboptimum method, respectively. The results indicate MLBP has superior prediction performance on the multi-functional peptides identification. MLBP is available at https://github.com/xialab-ahu/MLBP and http://bioinfo.ahu.edu.cn/MLBP/.

Alared: Solvatochromic and Fluorogenic Red Amino Acid for Ratiometric Live-Cell Imaging of Bioactive Peptides.

To fill the need for environmentally sensitive fluorescent unnatural amino acids able to operate in the red region of the spectrum, we have designed and synthesized Alared, a red solvatochromic and fluorogenic amino acid derived from the Nile Red chromophore. The new unnatural amino acid can be easily integrated into bioactive peptides using classical solid-phase peptide synthesis. The fluorescence quantum yield and the emission maximum of Alared-labeled peptides vary in a broad range depending on the peptide's environment, making Alared a powerful reporter of biomolecular interactions. Due to its red-shifted absorption and emission spectra, Alared-labeled peptides could be followed in living cells with minimal interference from cellular autofluorescence. Using ratiometric fluorescence microscopy, we were able to track the fate of the Alared-labeled peptide agonists of the apelin G protein-coupled receptor upon receptor activation and internalization. Due to its color-shifting environmentally sensitive emission, Alared allowed for distinguishing the fractions of peptides that are specifically bound to the receptor or unspecifically bound to different cellular membranes.

Whole genome sequencing analysis of Limosilactobacillus reuteri from the intestinal tract of mice recovering from ulcerative colitis and preliminary study on anti-inflammatory effects of its derived peptides.

Limosilactobacillus reuteri is an indigenous inhabitant of the animal gut known for its probiotic effects on the host. In our previous study, a large number of L. reuteri strains were isolated from the gastrointestinal tract of mice recovering from ulcerative colitis, from which we randomly selected L. reuteri RE225 for whole genome sequencing to explore its probiotic properties. The results of next-generation sequencing and third-generation single molecule sequencing showed that L. reuteri RE225 contained many genes encoding functional proteins associated with adhesion, anti-inflammatory and pathogen inhibition. And compared to other L. reuteri strains in NCBI, L. reuteri RE225 has unique gene families with probiotic functions. In order to further explore the probiotic effect of the L. reuteri RE225, the derived peptides were identified by LC-MS/MS, and the peptides with tumor necrosis factor-α binding ability were screened by reverse molecular docking and microscale thermophoresis. Finally, cell experiments demonstrated the anti-inflammatory ability of the peptides. Western blotting and qPCR analyses confirmed that the selected peptides might alleviate LPS-induced inflammation in NCM460 cells by inhibiting JAK2/STAT3 pathway activation.

Food-derived peptides unleashed: emerging roles as food additives beyond bioactivities.

Innovating food additives stands as a cornerstone for the sustainable evolution of future food systems. Peptides derived from food proteins exhibit a rich array of physicochemical and biological attributes crucial for preserving the appearance, flavor, texture, and nutritional integrity of foods. Leveraging these peptides as raw materials holds great promise for the development of novel food additives. While numerous studies underscore the potential of peptides as food additives, existing reviews predominantly focus on their biotic applications, leaving a notable gap in the discourse around their abiotic functionalities, such as their physicochemical properties. Addressing this gap, this review offers a comprehensive survey of peptide-derived food additives in food systems, accentuating the application of peptides' abiotic properties. It furnishes a thorough exploration of the underlying mechanisms and diverse applications of peptide-derived food additives, while also delineating the challenges encountered and prospects for future applications. This well-time review will set the stage for a deeper understanding of peptide-derived food additives.

In vitro strategies to understand the impact of oral intake on the bioavailability and bioactivity of peptides from brewing by-products.

Bioactive peptides from brewer's spent grain (BSG) and brewer's spent yeast (BSY), two by-products of the brewing industry, have great potential as functional food ingredients, dietary supplements or nutraceuticals to reduce the risk of numerous pathological conditions. Nevertheless, the oral administration of these peptides poses great challenges since peptides must undergo gastrointestinal digestion, intestinal absorption and hepatic metabolism, which can affect their bioavailability and, therefore, the expected outcomes. This review provides a comprehensive and critical analysis of the potential impact of the oral route on the bioactivity of BSG/BSY peptides as assessed by in vitro assays and identifies research gaps that require novel approaches/methodologies. The data collected indicate that in addition to the significant influence of gastrointestinal digestion, intestinal absorption and hepatic metabolism also have a major impact on the bioactivity of brewing peptides. The major gap identified was the insufficient evidence regarding hepatic metabolism, which points for the need of employing in vitro assays in this research field to provide such clarification. Thus, to reach the market, the impact of the oral route on the bioactivities of BSG/BSY peptides must be properly studied in vitro to allow adequate/effective administration (dosage/frequency) with a beneficial impact on the population health.

Bioinformatics tools for the study of bioactive peptides from vegetal sources: evolution and future perspectives.

Bioactive peptides from vegetal sources have been shown to have functional properties as anti-inflammatory, antioxidant, antihypertensive or antidiabetic capacity. For this reason, they have been proposed as an interesting and promising alternative to improve human health. In recent years, the numerous advances in the bioinformatics field for in silico prediction have speeded up the discovery of bioactive peptides, also reducing the associated costs when using an integrated approach between the classical and bioinformatics discovery. This review aims to provide an overview of the evolution, limitations and latest advances in the field of bioinformatics and computational tools, and specifically make a critical and comprehensive insight into computational techniques used to study the mechanism of interaction that allows the explanation of plant bioactive peptide functionality. In particular, molecular docking is considered key to explain the different functionalities that have been previously identified. The assumptions to simplify such a high complex environment implies a degree of uncertainty that can only be guaranteed and validated by in vitro or in vivo studies, however, the combination of databases, software and bioinformatics applications with the classical approach has become a promising procedure for the study of bioactive peptides.

Reactivity of amino acids and short peptide sequences: identifying bioactive compounds via DFT calculations.

Bioactive peptides are short amino acid sequences that play important roles in various physiological processes, including antioxidant and protective effects. These compounds can be obtained through protein hydrolysis and have a wide range of potential applications in a variety of areas. However, despite the potential of these compounds, more in-depth knowledge is still necessary to better understand details regarding their chemical reactivity and electronic properties. In this study, we used molecular modeling techniques to investigate the electronic structure of isolated amino acids (AA) and short peptide sequences. Details on the relative alignments between the frontier electronic levels, local chemical reactivity and donor-acceptor properties of the 20 primary amino acids and some di- and tripeptides were evaluated in the framework of the density functional theory (DFT). Our results suggest that the electronic properties of isolated amino acids can be used to interpret the reactivity of short sequences. We found that aromatic and charged amino acids, as well as Methionine, play a key role in determining the local reactivity of peptides, in agreement with experimental data. Our analyses also allowed us to identify the influence of the relative position of AA and terminations on the local reactivity of the sequences, which can guide experimental studies and help to propose/evaluate possible mechanisms of action. In summary, our data indicate that the position of active sites of polypeptides can be predicted from short sequences, providing a promising strategy for the synthesis and bioprospection of new optimized compounds.

Chromogranin A and its derived peptides: potential regulators of cholesterol homeostasis.

Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies.

Innovative Bioactive Products with Medicinal Value from Microalgae and Their Overall Process Optimization through the Implementation of Life Cycle Analysis-An Overview.

Microalgae are being recognized as valuable sources of bioactive chemicals with important medical properties, attracting interest from multiple industries, such as food, feed, cosmetics, and medicines. This review study explores the extensive research on identifying important bioactive chemicals from microalgae, and choosing the best strains for nutraceutical manufacturing. It explores the most recent developments in recovery and formulation strategies for creating stable, high-purity, and quality end products for various industrial uses. This paper stresses the significance of using Life Cycle Analysis (LCA) as a strategic tool with which to improve the entire process. By incorporating LCA into decision-making processes, researchers and industry stakeholders can assess the environmental impact, cost-effectiveness, and sustainability of raw materials of several approaches. This comprehensive strategy will allow for the choosing of the most effective techniques, which in turn will promote sustainable practices for developing microalgae-based products. This review offers a detailed analysis of the bioactive compounds, strain selection methods, advanced processing techniques, and the incorporation of LCA. It will serve as a valuable resource for researchers and industry experts interested in utilizing microalgae for producing bioactive products with medicinal properties.

Protein Hydrolysis as a Way to Valorise Squid-Processing Byproducts: Obtaining and Identification of ACE, DPP-IV and PEP Inhibitory Peptides.

The industrial processing of Argentine shortfin squid to obtain rings generates a significant amount of protein-rich waste, including the skin, which is rich in collagen and attached myofibrillar proteins. This waste is generally discarded. In this study, skin was used as a source of proteins that were hydrolysed using Trypsin, Esperase® or Alcalase®, which released peptides with antioxidant potential and, in particular, antihypertensive (ACE inhibition), hypoglycemic (DPP-IV inhibition) and/or nootropic (PEP inhibition) potential. Among the three enzymes tested, Esperase® and Alcalase produced hydrolysates with potent ACE-, DPP-IV- and PEP-inhibiting properties. These hydrolysates underwent chromatography fractionation, and the composition of the most bioactive fractions was analysed using HPLC-MS-MS. The fractions with the highest bioactivity exhibited very low IC50 values (16 and 66 µg/mL for ACE inhibition, 97 µg/mL for DPP-IV inhibition and 55 µg/mL for PEP inhibition) and were mainly derived from the hydrolysate obtained using Esperase®. The presence of Leu at the C-terminal appeared to be crucial for the ACE inhibitory activity of these fractions. The DPP-IV inhibitory activity of peptides seemed to be determined by the presence of Pro or Ala in the second position from the N-terminus, and Gly and/or Pro in the last C-terminal positions. Similarly, the presence of Pro in the peptides present in the best PEP inhibitory fraction seemed to be important in the inhibitory effect. These results demonstrate that the skin of the Argentine shortfin squid is a valuable source of bioactive peptides, suitable for incorporation into human nutrition as nutraceuticals and food supplements.

Glucoregulatory Properties of a Protein Hydrolysate from Atlantic Salmon (Salmo salar): Preliminary Characterization and Evaluation of DPP-IV Inhibition and Direct Glucose Uptake In Vitro.

Metabolic disorders are increasingly prevalent conditions that manifest pathophysiologically along a continuum. Among reported metabolic risk factors, elevated fasting serum glucose (FSG) levels have shown the most substantial increase in risk exposure. Ultimately leading to insulin resistance (IR), this condition is associated with notable deteriorations in the prognostic outlook for major diseases, including neurodegenerative diseases, cancer risk, and mortality related to cardiovascular disease. Tackling metabolic dysfunction, with a focus on prevention, is a critically important aspect for human health. In this study, an investigation into the potential antidiabetic properties of a salmon protein hydrolysate (SPH) was conducted, focusing on its potential dipeptidyl peptidase-IV (DPP-IV) inhibition and direct glucose uptake in vitro. Characterization of the SPH utilized a bioassay-guided fractionation approach to identify potent glucoregulatory peptide fractions. Low-molecular-weight (MW) fractions prepared by membrane filtration (MWCO = 3 kDa) showed significant DPP-IV inhibition (IC50 = 1.01 ± 0.12 mg/mL) and glucose uptake in vitro (p ≤ 0.0001 at 1 mg/mL). Further fractionation of the lowest MW fractions (<3 kDa) derived from the permeate resulted in three peptide subfractions. The subfraction with the lowest molecular weight demonstrated the most significant glucose uptake activity (p ≤ 0.0001), maintaining its potency even at a dilution of 1:500 (p ≤ 0.01).

Bioactivity and volatile compound evaluation in sheep milk processed by ohmic heating.

Ohmic heating may improve bioactive compounds and processing, ensuring food safety of beverages, liquid and pasty food, or liquid with solid pieces. Due to those traits, this study conducted a comparison between ohmic heating technology and conventional heating (CH), with a focus on assessing the impact of both methods on functional compounds (such as angiotensin-converting enzyme inhibition, α-amylase and α-glucosidase inhibition, and antioxidant activity) in both fresh and thawed raw sheep milk, which had been frozen for up to 3 mo. Different ohmic heating conditions were applied and compared to CH (3.33-8.33 V/cm vs. CH [73°C/15 s]). A total of 18 peptides with some functional activities were identified by MALDI-TOF mass spectrometry analysis. Ohmic heating samples presented the highest activities related to health, followed by CH and raw milk samples; antioxidant activity range was from 0.11% to 0.71%, antihypertensive activity ranged from 0.20% to 0.72%, and antidiabetic activity ranged from 0.21% to 0.79%. Of 51 volatile compounds detected, some were degraded by freezing, storing, and heating the sheep milk. This study showed for the first time that ohmic heating processing improved sheep milk bioactive peptides and preserved volatile compounds.

Invited review: Camel milk-derived bioactive peptides and diabetes-Molecular view and perspectives.

In dairy science, camel milk (CM) constitutes a center of interest for scientists due to its known beneficial effect on diabetes as demonstrated in many in vitro, in vivo, and clinical studies and trials. Overall, CM had positive effects on various parameters related to glucose transport and metabolism as well as the structural and functional properties of the pancreatic ß-cells and insulin secretion. Thus, CM consumption may help manage diabetes; however, such a recommendation will become rationale and clinically conceivable only if the exact molecular mechanisms and pathways involved at the cellular levels are well understood. Moreover, the application of CM as an alternative antidiabetic tool may first require the identification of the exact bioactive molecules behind such antidiabetic properties. In this review, we describe the advances in our knowledge of the molecular mechanisms reported to be involved in the beneficial effects of CM in managing diabetes using different in vitro and in vivo models. This mainly includes the effects of CM on the different molecular pathways controlling (1) insulin receptor signaling and glucose uptake, (2) the pancreatic ß-cell structure and function, and (3) the activity of key metabolic enzymes in glucose metabolism. Moreover, we described the current status of the identification of CM-derived bioactive peptides and their structure-activity relationship study and characterization in the context of molecular markers related to diabetes. Such an overview will not only enrich our scientific knowledge of the plausible mode of action of CM in diabetes but should ultimately rationalize the claim of the potential application of CM against diabetes. This will pave the way toward new directions and ideas for developing a new generation of antidiabetic products taking benefits from the chemical composition of CM.

Molecular docking studies on α-amylase inhibitory peptides from milk of different farm animals.

Milk-derived peptides have emerged as a popular mean to manage various lifestyle disorders such as diabetes. Fermentation is being explored as one of the faster and efficient way of producing peptides with antidiabetic potential. Therefore, in this study, an attempt was made to comparatively investigate the pancreatic α-amylase (PAA) inhibitory properties of peptides derived from milk of different farm animals through probiotic fermentation. Peptide's identification was carried out using liquid chromatography-quadrupole time-of-flight mass spectrometry and inhibition mechanisms were characterized by molecular docking. Results obtained showed a PAA-IC50 value (the amount of protein equivalent needed to inhibit 50% of enzymes) between 2.39 and 36.1 µg protein equivalent for different fermented samples. Overall, Pediococcus pentosaceus MF000957-derived fermented milk from all animals indicated higher PAA inhibition than other probiotic derived fermented milk (PAA-IC50 values of 6.01, 3.53, 15.6, and 10.8 µg protein equivalent for bovine, camel, goat, and sheep fermented milk). Further, molecular docking analysis indicated that camel milk-derived peptide IMEQQQTEDEQQDK and goat milk-derived peptide DQHQKAMKPWTQPK were the most potent PAA inhibitory peptides. Overall, the study concluded that fermentation derived peptides may prove useful in for managing diabetes via inhibition of carbohydrate digesting enzyme PAA.

An Integrated Comprehensive Peptidomics and In Silico Analysis of Bioactive Peptide-Rich Milk Fermented by Three Autochthonous Cocci Strains.

Bioactive peptides (BPs) are molecules of paramount importance with great potential for the development of functional foods, nutraceuticals or therapeutics for the prevention or treatment of various diseases. A functional BP-rich dairy product was produced by lyophilisation of bovine milk fermented by the autochthonous strains Lactococcus lactis subsp. lactis ZGBP5-51, Enterococcus faecium ZGBP5-52 and Enterococcus faecalis ZGBP5-53 isolated from the same artisanal fresh cheese. The efficiency of the proteolytic system of the implemented strains in the production of BPs was confirmed by a combined high-throughput mass spectrometry (MS)-based peptidome profiling and an in silico approach. First, peptides released by microbial fermentation were identified via a non-targeted peptide analysis (NTA) comprising reversed-phase nano-liquid chromatography (RP nano-LC) coupled with matrix-assisted laser desorption/ionisation-time-of-flight/time-of-flight (MALDI-TOF/TOF) MS, and then quantified by targeted peptide analysis (TA) involving RP ultrahigh-performance LC (RP-UHPLC) coupled with triple-quadrupole MS (QQQ-MS). A combined database and literature search revealed that 10 of the 25 peptides identified in this work have bioactive properties described in the literature. Finally, by combining the output of MS-based peptidome profiling with in silico bioactivity prediction tools, three peptides (75QFLPYPYYAKPA86, 40VAPFPEVFGK49, 117ARHPHPHLSF126), whose bioactive properties have not been previously reported in the literature, were identified as potential BP candidates.

Olive Pomace Extract Contains Low Molecular Weight Peptides and Possesses ACE Inhibitory Activity.

The aim of the present study was to determine the ACE inhibitory activity of aqueous extracts of olive pomace and to understand whether they represent a good source of bioactive LMW peptides for nutritional and pharmacological applications. We produced a water extract from olive pomace (var. Picual) and obtained its low molecular weight (LMW) fraction (<3 kDa). The calculated yield of extraction was 100.2 ± 7.9 mg of LMW peptides per 100 g of olive pomace. The olive pomace LMW fraction possessed strong ACE inhibitory activity (IC50 = 3.57 ± 0.22 µg prot/mL). The LMW fraction (<3 kDa) was analysed by nanoscale liquid chromatography-Orbitrap coupled with tandem mass spectrometry and de novo sequencing. Thirty new peptides, containing between 7-17 amino acids and molecular masses ranging 778-1354 Da, were identified by the Peaks database algorithm using the available Olea europaea (cv. Farga) genome database. Ten new peptides were also identified by Peaks de novo sequencing. The protein sources of twelve peptides detected in the database by Peaks DB were identified by BLAST search. The ACE inhibitory activity of the identified peptides was predicted by BIOPEP software. We conclude that olive pomace possesses ACE inhibitory activity and contains low molecular weight peptides with (predicted) biological activity. Olive pomace may represent a good source of peptides for nutritional and pharmaceutical applications. In our study, it has been shown that olive pomace possesses ACE inhibitory activity and contains low molecular weight peptides with (predicted) biological activity. Olive pomace may represent a good source of peptides for nutritional and pharmaceutical applications. More research is needed in order to identify the in vivo effects of olive pomace bioactive peptides.

Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools.

Over the last few decades, we have witnessed growing interest from both academic and industrial laboratories in peptides as possible therapeutics. Bioactive peptides have a high potential to treat various diseases with specificity and biological safety. Compared to small molecules, peptides represent better candidates as inhibitors (or general modulators) of key protein-protein interactions. In fact, undruggable proteins containing large and smooth surfaces can be more easily targeted with the conformational plasticity of peptides. The discovery of bioactive peptides, working against disease-relevant protein targets, generally requires the high-throughput screening of large libraries, and in silico approaches are highly exploited for their low-cost incidence and efficiency. The present review reports on the potential challenges linked to the employment of peptides as therapeutics and describes computational approaches, mainly structure-based virtual screening (SBVS), to support the identification of novel peptides for therapeutic implementations. Cutting-edge SBVS strategies are reviewed along with examples of applications focused on diverse classes of bioactive peptides (i.e., anticancer, antimicrobial/antiviral peptides, peptides blocking amyloid fiber formation).