Bioactive peptides derived from fish have garnered significant attention due to their diverse physiological activities and potential applications in functional foods and therapeutics. These peptides are obtained through enzymatic hydrolysis of fish muscle and processing by-products, displaying strong antimicrobial and antioxidative properties.

Peptides extracted from fish by-products have demonstrated efficacy in preventing oxidative damage and enhancing food preservation, showcasing their applicability as natural food additives [1]. Notable findings include peptides such as F21, derived from Gadidae fish muscle, which demonstrates antioxidant activity with an IC50 value of 389.9 µg/mL (DPPH) and strong angiotensin-converting enzyme (ACE) inhibitory properties [2]. Another peptide, an ACE inhibitor from skipjack-tuna, Ser-Pro (SP), effectively regulates blood pressure and shows bioactive potential in cardiovascular health [3].

This review focuses the progress in identifying, isolating, and characterizing bioactive peptides from fish, demonstrating their potential to improve health and support innovative solutions in the food and pharmaceutical industries.

[1] Najafian et al., 2012. Peptides, 33: 178-185

[2] Maky et al., 2021. Applied Sciences.

[3] Zheng et al., 2022. Marine Drugs, 20.

The rapid growth of antimicrobial resistance is a pressing public health concern that requires the discovery of novel antibiotics. Recently, antimicrobial peptides that inhibit undrugged bacterial pathways have been identified leading many to believe that synthetic antimicrobial peptides may serve to combat antimicrobial resistance. Our research seeks to understand the molecular mechanism outlining the antimicrobial peptide, Pdi1, which binds the bacterial ribosome. To investigate the Pdi1-ribosome interaction, we developed a biolayer interferometry pipeline to measure binding rates and affinity. Peptides were synthesized via solid-phase peptide synthesis and N-terminally biotinylated with biotin-PEG₂₄-NHS ester. Biotinylated peptides were suspended on streptavidin coated biosensors and exposed to increasing concentrations of purified ribosome to measure association and dissociation. Our binding data indicates that Pdi1 binds the bacterial ribosome with a picomolar binding affinity and demonstrates a remarkably slow off-rate. Additional studies of Pdi1 peptides containing alanine substitutions revealed that replacement of residues 14, 18, and 19 resulted in significantly decreased binding response. Our results suggest that these residues make necessary contacts with the ribosome and make significant contributions to Pdi1 binding affinity. These data serve as a foundation for future peptide-based structure-activity relationship campaigns and the development of potent Pdi1 analogues.

Triple-negative breast cancer (TNBC) is an aggressive and challenging subtype of breast cancer characterized by absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor-2 (HER2). While chemotherapy remains the most common treatment for TNBC, its limitations—including recurrence, metastasis, and resistance—underscore the need for combination therapeutic strategies such as immunotherapy. Host defense peptides (HDPs), are a class of naturally occurring compounds with emerging anticancer potential. Since HDPs are known to play a critical role in modulating immune responses, we designed and developed disulfide bridge-linked antimicrobial peptides (termed mCA4) based on host defense protein chicken Angiogenin 4 (chAng4). mCA4 demonstrated significant potential to re-polarize RAW-264.7 murine macrophages from pro-tumorigenic phenotype to anti-tumorigenic phenotype. Treatment of macrophages with mCA4 resulted in increased expression of pro-inflammatory cytokines (TNF-α, IL-1β) and a decreased expression of anti-inflammatory cytokines (IL-10, TGF-β). Co-culturing mCA4 activated RAW-264.7 macrophages with TNBC cells (4T1) led to suppression of anti-inflammatory pathways (STAT-3 and STAT-6) and activation of a pro-inflammatory pathway (STAT-1), resulting in significantly increased apoptosis of TNBC compared to treatment with doxorubicin (DOX) alone in-vitro. These findings suggest that mCA4 may offer a promising therapeutic strategy for reprogramming the immune microenvironment in TNBC and enhancing anti-tumor immunity.

Cancer is a major public health concern which resulted in almost 10 million deaths in the year 2022. Traditional modes of treatment like surgery, radiotherapy and chemotherapy cause substantial side-effects and are not efficacious in metastatic cancer conditions. Drug delivery methods provide the possibility of specifically targeting cancer, minimizing the damage to non-cancerous cells. One such mode of drug delivery is the utilization of cell-penetrating peptides (CPPs) which can travel across the cellular membrane and enter the cell. These CPPs can be conjugated to a wide range of cargo molecules for intracellular delivery. In this work, we have designed and synthesized a series of peptides based on their electrostatic features to specifically deliver an anti-cancer drug molecule to cancer cells and drug resistant cancer cells. The penetrative ability and cancer cell cytotoxicity of the CPP-drug conjugate was tested using in-vitro studies. The conjugates also showed significant tumor reduction in breast cancer mice models. Thus, our designed peptide-based delivery vectors present a novel approach for targeting cancer and cancer drug resistance.

In this study, we present a novel therapeutic approach for colorectal cancer by integrating oncolytic virotherapy with a peptide-based immune checkpoint inhibitor. We previously engineered a synthetic chimeric virus (VMG) that expresses the glycoprotein (G) from Morreton virus (MorV) while retaining the structural genes from vesicular stomatitis virus (VSV). Additionally, a 12-amino acid linear peptide, identified through phage display biopanning, was found to inhibit the CD47/SIRPα interaction, thereby enhancing macrophage-mediated phagocytosis of tumor cells. The antitumor efficacy of this combination therapy was evaluated in two syngeneic mouse models, CT26 and MC38. Our findings demonstrate that the combined treatment significantly prolonged survival and delayed tumor growth in both CT26 and MC38 tumor-bearing mice.

Trimethyllysine (Kme3) is a post-translational modification on histones which regulates gene expression, often via binding of reader proteins. Many human Kme3 readers have been identified, often binding the same histone sequence but with different biological implications. Many readers are therapeutic targets, but selective inhibition of these conserved binding motifs remains challenging. Reader proteins universally bind Kme3 in an aromatic cage. Typically, this binding is attributed to cation-π interactions but recently exceptions have been suggested. We investigated the generality of this assumption with the goal of providing insight into novel approaches for selective inhibition. We utilized biophysical, mechanistic, and structural studies to discover that the ability of readers to bind the neutral isostere of Kme3 (tBuNle) is more widespread than previously thought: ~5% of human proteins in this class. This discovery establishes a new framework for selective inhibitor design by exploiting differences in charge-dependence among readers. We find that readers that bind both Kme3 and tBuNle do so through different mechanisms, utilizing cation-π interactions to recognize the former and solely the hydrophobic effect to bind the latter. This finding is significant, as these readers represent rare examples of proteins recognizing differently charged ligands in the same binding site via distinct mechanisms.

Protein phosphatase 5 (PP5) recruited to its substrates by molecular chaperone HSP70 and HSP90 interaction. This interaction requires HSP70/HSP90 c- terminal EEVD motif and PP5’ TPR domain. Since, PP5 has a broad array of substrates however how PP5 shows selectivity toward its substrate is still a lacunae. To know its molecular determinants, we screened a large, pentapeptide library which contain 640,000 possible EEVD-like sequences. Affinity and melting temperature analysis of PP5 with pentapeptide library shows the preference for bulky amino acid at certain position. This analysis led to the exploration of EEVD like motif in human proteome, analysis led to the identification of 4 proteins ELP1, DDCP, U520 and AGO1 have EEVD-like motif in its C-termini. Affinity analysis of these protein c-terminal motif shows only ELP1 as an interacting partner to PP5. This led us to know the chaperone involvement in PP5:ELP1 interaction. Co-IP reveal absence of HSP90/HSP70 in this PP5:ELP1 interaction, suggest the chaperone independent interaction with ELP1. This finding reveals PP5 ability to work chaperone independently.

There is a great demand for the development of synthetic systems for mimicking bioinspired chemical reactions without utilizing complex enzymes in their native state. Peptide-based nanomaterials offer significant potential as a component for the construction of artificial enzymes. In this study, we investigated the catalytic activity of self-assembly of three tripeptides, P1, P2, and P3 as a hydrolase model. Here, self-assembled peptide P3 has shown the highest catalytic activity with a chromogenic substrate, p-nitrophenyl acetate. Moreover, our findings indicate that the catalytic activity of peptides has been increased with an increase in pH and temperature levels. As similar to native enzyme, these peptide-mimics have shown different specificity towards a series of substrates. By employing rheological studies of peptide hydrogels, we confirm that the strength of the hydrogel of peptide P3 with the highest catalytic activity is the least among all the three tripeptides. Consequently, it indicates that the strength of peptide hydrogel is inversely proportional to the catalytic activity of peptide hydrogel. The viability of HEK-293 cells remained largely unaffected by elevated peptide concentrations, indicating that these molecular systems exhibit substantial biocompatibility. Overall, this study provides insights into how the positioning of histidine residue modulate the catalytic activity of tripeptides.

The study investigated the nutraceutical potential of whey fermented with Saccharomyces boulardii, emphasizing its effects on inflammatory and immunological responses in an animal model. Fermented whey was obtained through yeast activation and incubation at 30°C for 24 hours, followed by a 12-hour fermentation process, with subsequent centrifugation to remove microorganisms. In vivo experiments (CEUA/UDESC no. 3728250923) involved 15 female cats, divided into a Control group (8 animals) and a Treatment group (7 animals) that received fermented whey mixed with feed at a concentration of 0.59% for 20 days. Peptidomic analysis identified 715 peptides in digested fermented whey, with 15.21% exhibiting antioxidant potential. Anti-inflammatory predictions revealed a higher prevalence of high-confidence peptides. Blood analysis demonstrated a reduction in leukocytes (from 11.7 × 10³/µL to 6.31 × 10³/µL), an increase in lymphocytes (from 3.73 × 10³/µL to 7.6 × 10³/µL), and a decrease in ferritin (from 23.3 ng/mL to 6.3 ng/mL), indicating reduced inflammation. Albumin showed a slight improvement (from 2.34 to 2.50 g/dL), while C-reactive protein levels remained stable. The results indicate that peptides from fermented whey can modulate immune responses and decrease inflammatory markers, suggesting therapeutic potential for chronic inflammation and supporting its use as a functional food.

Many diseases are associated with insoluble amyloid deposits in various tissues, including Alzheimer’s disease and type II diabetes. To achieve its insoluble cross-b structure, the protein precursor undergoes a multitude of transient conformational transitions, making the development of specific therapy against amyloidosis particularly challenging. The chaperones heat shock proteins of 70 kDa (Hsp70) have been identified as potent inhibitors of amyloid aggregation. Herein, the islet amyloid polypeptide (IAPP) is used as a model amyloidogenic peptide to characterize the mechanism of inhibition by the Hsp70 Binding immunoglobulin protein (BiP), which is composed of a nucleotide binding domain (NBD) and of a peptide binding domain divided into two subunits (SBDα and SBDβ). BiP hydrolyzes adenosine triphosphate (ATP) to change its conformation isolating the client protein, but can also work in the absence of ATP, without modifying its conformation. Full-length BiP, SBDα and SBDβ subunits were recombinantly expressed to identify the domain responsible for the inhibition of amyloid aggregation of IAPP in the absence of ATP. Biophysical analyzes supported by computational approaches show that the complete structure of BiP is necessary for amyloid inhibition. By further characterizing the residues implicated in this interaction, this project will support the design of new therapeutics.