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Across internally fertilising species, males transfer ejaculate proteins that trigger wide-ranging changes in female behaviour and physiology. Much theory has been developed to explore the drivers of ejaculate protein evolution. The accelerating availability of high-quality genomes now allows us to test how these proteins are evolving at fine taxonomic scales. Here, we use genomes from 264 species to chart the evolutionary history of Sex Peptide (SP), a potent regulator of female post-mating responses in Drosophila melanogaster. We infer that SP first evolved in the Drosophilinae subfamily and has since followed markedly different evolutionary trajectories in different lineages. Outside of the Sophophora-Lordiphosa, SP exists largely as a single-copy gene with independent losses in several lineages. Within the Sophophora-Lordiphosa, the SP gene family has repeatedly and independently expanded. Up to seven copies, collectively displaying extensive sequence variation, are present in some species. Despite these changes, SP expression remains restricted to the male reproductive tract. Alongside, we document considerable interspecific variation in the presence and morphology of seminal microcarriers that, despite the critical role SP plays in microcarrier assembly in D. melanogaster, appears to be independent of changes in the presence/absence or sequence of SP. We end by providing evidence that SP's evolution is decoupled from that of its receptor, Sex Peptide Receptor, in which we detect no evidence of correlated diversifying selection. Collectively, our work describes the divergent evolutionary trajectories that a novel gene has taken following its origin and finds a surprisingly weak coevolutionary signal between a supposedly sexually antagonistic protein and its receptor.

The popularity of Glycosaminoglycans (GAGs) in drug delivery systems has grown as their innate ability to sequester and release charged molecules makes them adept in the controlled release of therapeutics. However, peptide therapeutics have been relegated to synthetic, polymeric systems, despite their high specificity and efficacy as therapeutics because they are rapidly degraded in vivo when not encapsulated. We present a GAG-based nanoparticle system for the easy encapsulation of cationic peptides, which offers control over particle diameter, peptide release behavior, and swelling behavior, as well as protection from proteolytic degradation, using a singular, organic polymer and no covalent linkages. These nanoparticles can encapsulate cargo with a particle diameter range spanning 130-220 nm and can be tuned to release cargo over a pH range of 4.5 to neutral through the modulation of the degree of sulfation and the molecular weight of the GAG. This particle system also confers better in vitro performance than the unencapsulated peptide via protection from enzymatic degradation. This method provides a facile way to protect therapeutic peptides via the inclusion of the presented binding sequence and can likely be expanded to larger, more diverse cargo as well, abrogating the complexity of previously demonstrated systems while offering broader tunability.

METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor RM3, which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin‐mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno‐related genes following RM3‐mediated suppression of METTL3/14 N6‐methyladenosine (m6A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti‐PD‐1 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase RM3, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection, and viral genes are poised to be transcribed in the latent chromatin. In the poised chromatins, KSHV latency-associated nuclear antigen (LANA) interacts with cellular chromodomain-helicase-DNA-binding protein 4 (CHD4) and inhibits viral promoter activation. CHD4 is known to regulate cell differentiation by preventing enhancers from activating promoters. Here, we identified a putative CHD4 inhibitor peptide (VGN73) from the LANA sequence corresponding to the LANA-CHD4 interaction surface. The VGN73 interacts with CHD4 at its PHD domain with a dissociation constant (K D) of 14 nM. Pre-treatment with VGN73 enhanced monocyte differentiation into macrophages and globally altered the repertoire of activated genes in U937 cells. Furthermore, the introduction of the peptide into the cancer cells induced caspase-mediated CHD4 cleavage, triggered cell death, and inhibited tumor growth in a xenograft mouse model. The VGN73 may facilitate cell differentiation therapy. [Display omitted] • VGN73 derived from KSHV LANA protein sequence interacts with and induces CHD4 cleavage • LANA peptide induces cell apoptosis and autophagy by CHD4 cleavage • VGN73 facilitates transcription reprogramming of monocytes • VGN73 prevents primary effusion lymphoma cell growth in a xenograft model Miura et al. identify a small peptide, derived from the KSHV LANA protein sequence, that enhances monocyte differentiation into macrophages. The introduction of the peptide into cancer cells induces CHD4 protein cleavage, triggers cell death, and inhibits tumor growth in a xenograft mouse model. [ABSTRACT FROM AUTHOR]

Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the h 2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface. Additionally, our data suggest that DEDid targets other type I DED interactions such as those of FADD. Both approaches of blocking type I DED interactions inhibited CD95L-induced DISC assembly, caspase activation and apoptosis. We showed that inhibition of procaspase-8 type I interactions by mutations not only diminished procaspase-8 recruitment to the DISC but also destabilized the FADD core of DED filaments. Taken together, this study offers insights to develop strategies to target DED proteins, which may be considered in diseases associated with cell death and inflammation. [Display omitted] • A rationally designed peptide, DEDid, was engineered to target type I DED interactions • DEDid mimics the h 2b of procaspase-8-DED2 containing a highly conservative FL motif • Targeting type I DED interactions inhibited DED filament assembly and apoptosis • Assembly of the DED proteins at the DISC occurs in a cooperative manner König, Ivanisenko, and Hillert-Richter et al. develop a cell-penetrating peptide, DEDid, that targets the type I interface of procaspase-8 and DED protein FADD. DEDid inhibits DED filament assembly, caspase activation, and apoptosis. This study opens promising avenues for developing future strategies to target DED proteins associated with cell death and inflammation. [ABSTRACT FROM AUTHOR]

Voltage-gated potassium channels play a crucial role in cellular repolarization and are potential therapeutic targets in neuroinflammatory disorders and neurodegenerative diseases. This study explores Tityus bahiensis scorpion venom for neuroactive peptides. We identified the αKtx12 peptide as a potent neuroprotective agent. In SH-SY5Y cells, αKtx12 significantly enhances viability, validating its pharmacological potential. And in the animal model, we elucidate central nervous system (CNS) mechanism of αKtx12 through neuroproteomic analyses highlighting αKtx12 as a valuable tool for characterizing neuroplasticity and neurotropism, revealing its ability to elicit more physiological responses. The peptide's potential to promote cell proliferation and neuroprotection suggests a role in functional recovery from nervous system injury or disease. This research unveils the neuroactive potential of scorpion venom-derived αKtx12's, offering insights into its pharmacological utility. The peptide's impact on neuronal processes suggests a promising avenue for therapeutic development, particularly in neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: TAG‐assisted peptide synthesis technology enables optimal conservation of Fmoc amino acid raw materials and chemical solvents while eliminating the need for intricate chromatographic purification processes. This work presents a 4,4'‐diphenylphosphonoxy diphenylcarbinol tag‐mediated liquid‐phase synthesis approach for preparing side‐to‐tail cyclopeptides macolacin which has strong activity against gram‐negative bacteria, and its 15 analogues containing four N‐methylation modified cyclopeptides, as well as an investigation of their structure‐activity relationship (SAR). The synthesis of macolacin analogues primarily focuses on the modifications of the N‐methylation group of Ile‐7 and the tail fatty acyl chain of macolacin. The incorporation of N‐methylation for Ile‐7, along with the dihalogenated or monohalogenated benzoic acids for tail modification, exhibited remarkable antibacterial efficacy and minimal hepatocellular toxicity in vitro. The present study identified an N‐methylation‐modified antimicrobial cyclopeptide Ma14 that exhibits rapid bactericidal efficacy against A. baumanii, etc., while showing reduced hepatocellular toxicity. Molecular docking simulations were conducted to investigate the binding of cyclopeptides to the outer membrane protein BamA of A. baumannii. The findings demonstrated the stable binding interactions of the cyclopeptides with the BamA protein and then presented a novel approach to explain the bacteriostatic mechanism of macolacin‐based cyclopeptide antibiotics. [ABSTRACT FROM AUTHOR]

Cell-cell communication is essential for both unicellular and multicellular organisms. Secreted peptides that act as diffusive ligands are utilized by eukaryotic organisms to transduce information between cells to coordinate developmental and physiological processes. In plants, The CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) genes encode a family of secreted small peptides which play pivotal roles in stem cell homeostasis in various types of meristems. Accumulated evidence has revealed that CLE peptides mediate trans-kingdom interactions between plants and microbes, including pathogens and symbionts. This review highlights the emerging roles of CLE peptide signaling in plant-microbe interactions, focusing on their involvement in nodulation, immunity, and symbiosis with arbuscular mycorrhizal fungi. Understanding these interactions provides insights into the sophisticated regulatory networks to balance plant growth and defense, enhancing our knowledge of plant biology and potential agricultural applications. [ABSTRACT FROM AUTHOR]

Esophageal cancer is one of the most common cancers in the world, ranking sixth in cancer-related mortality. Doxorubicin (DOX), as a classic broad-spectrum, non-specific small-molecular anti-tumor drug, has achieved widespread use, including in the treatment of esophageal cancer. However, due to its strong cardiotoxicity, poor tumor-targeting ability, and short half-life, the clinical application of DOX has been greatly limited. In this research, we designed and successfully synthesized a peptide sequence IEIIIK (IEK for short) with excellent pH responsiveness. Under physiological conditions (pH 7.4), the peptide can encapsulate DOX and self-assemble into a stable hydrogel (DOX-IEK) through hydrophobic and electrostatic interactions. After being injected into the acidic tumor microenvironment, the protonation degree of alkaline amino acid lysine increased and the negative charge of glutamate decreased, directly leading to enhanced electrostatic repulsion and subsequent hydrogel dissociation. Released DOX can accumulate in tumor tissue and achieve anti-tumor efficacy. More importantly, the hydrogel can act as a drug reservoir for sustained drug release, improving the drug targeting ability, prolonging the duration of drug administration to compensate for the short half-life of DOX, and reducing systemic toxicity. Ideal anti-tumor efficacy has been achieved in both the in vitro and in vivo experiments. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a metabolic syndrome characterized by hyperglycaemia, polydipsia, polyuria, and weight loss, among others. The pathophysiology for the disorders is complex and results in pancreatic abnormal function. Viruses have also been implicated in the metabolic syndrome. This study charted peptides to investigate and predict the autoimmune potential of shared sequences between 8 viral species proteins (which we termed 'diabetes-viruses') and the human pancreatic proteins. The structure and immunological relevance of shared sequences between viruses reported in DM onset and human pancreatic proteins were analysed. At nonapeptide mapping between human pancreatic protein and 'diabetic-viruses', reveal 1064 shared sequences distributed among 454 humans and 4288 viral protein sequences. The viral results showed herpesviruses, enterovirus (EV), human endogenous retrovirus, influenza A viruses, rotavirus, and rubivirus sequences are hosted by the human pancreatic protein. The most common shared nonapeptide was AAAAAAAAA, present in 30 human nonredundant sequences. Among the viral species, the shared sequence NSLEVLFQG occurred in 18 nonredundant EVs protein, while occurring merely in 1 human protein, whereas LGLDIEIAT occurred in 8 influenza A viruses overlapping to 1 human protein and KDELSEARE occurred in 2 rotaviruses. The prediction of the location of the shared sequences in the protein structures, showed most of the shared sequences are exposed and located either on the surface or cleft relative to the entire protein structure. Besides, the peptides in the viral protein shareome were predicted computationally for binding to MHC molecules. Here analyses showed that the entire 1064 shared sequences predicted 203 to be either HLA-A or B supertype-restricted epitopes. Fifty-one of the putative epitopes matched reported HLA ligands/T-cell epitopes majorly coming from EV B supertype representative allele restrictions. These data, shared sequences, and epitope charts provide important insight into the role of viruses on the onset of DM and its implications. [ABSTRACT FROM AUTHOR]

The strategy of in vivo self‐assembly has been developed for improved enrichment and long‐term retention of anticancer drug in tumor tissues. However, most self‐assemblies with non‐covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling‐induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation‐responsive peptide‐porphyrin conjugate P1 is synthesized, which self‐assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2‐fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria‐targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) has been shown to have central nervous system effects. Although tissue renin-angiotensin systems (RAS) have been demonstrated in multiple tissues, the existence of a brain RAS is still a matter of debate. These studies test for angiotensin release from brain slices prepared from adult male Sprague-Dawley rats and male and female renin knock-out rats using Chinese hamster ovary cells modified to express both the angiotensin II type 1 receptor and a fluorescent calcium indicator. Sniffer cells were placed on the slices and calcium transients were measured from those located on or adjacent to the median preoptic nucleus with and without stimulation of the subfornical organ. Bath application of tetrodotoxin (1 µM) significantly attenuated spontaneous events while abolishing evoked sniffer cell activity. Bath application of dl -AP4 (10 µM, glutamatergic antagonist) did not affect either spontaneous or evoked release. Incubating the slices with fluorocitrate to inactive astrocytes did not influence sniffer cell activity in the MnPO. Pharmacological experiments indicate that ANG II release is largely both renin (aliskiren 10 µM) and ACE-1 (captopril 100 µM) dependent. However, experiments with brain slices prepared from male and female Renin knock-out rats suggest that alternative synthetic pathways may exist. Finally, these studies demonstrate that increases in ANG II release are observed following 7 days of chronic intermittent hypoxia. These studies suggest the existence of a tissue-specific RAS in the brain that involves canonical and alternative ANG II synthetic pathways and is upregulated in an animal model of sleep apnea. NEW & NOTEWORTHY: These studies used Chinese hamster ovary cells that were cloned to express an angiotensin receptor (At1ra) and a calcium indicator (R-GECO) to detect the release of angiotensin from brain slices containing the lamina terminalis of rats. Some of the experiments use tissue from renin knockout rats. The results support the existence of an angiotensin system in the brain that may involve alternative synthetic pathways and is upregulated by intermittent hypoxia. [ABSTRACT FROM AUTHOR]

Several bacterial strains have developed resistance against commercial antibiotics, and interestingly, supramolecular nanomaterials have shown considerable advantages for antibacterial applications. However, the main challenges in adopting nanotechnology for antibacterial studies are random aggregation, compromised toxicity, multi-step preparation approaches, and unclear structure-function properties. Herein, we designed the amphiphilic tripeptide that acts as a reducing and capping agent for silver metal to form silver-peptide colloidal nanohybrids with the mild assistance of UV light (254 nm) through the photochemical reduction method. The nanohybrids are characterized by different spectroscopic and microscopic techniques, and non-covalent molecular interactions between metal and peptide building blocks confirm their central role in the formation of nanohybrids. The tripeptide is biocompatible and can reduce the toxicity of silver ions (Ag+) by reducing to Ag0. These colloidal nanohybrids showed antibacterial activity against gram-negative and gram-positive bacterial strains, and the possible mechanism of killing bacterial cells could be membrane disruption. This synthetic strategy is facile and green, which helps avoid using toxic chemicals or reagents and complicated methods for colloidal nanohybrid preparation for biomedical applications. [ABSTRACT FROM AUTHOR]

Objective: Transcatheter Arterial Chemoembolization (TACE) is the first choice for the treatment of advanced-stage hepatocellular carcinoma (HCC). However, TACE suffers from a lack of specificity and rapid drug release. Herein, a targeted redox-responsive peptide (TRRP) was synthesized and used as a carrier of doxorubicin (DOX) to enhance the efficacy of TACE through tumor cells targeting and controlled drug release. Methods: TRRP has a high loading capacity of DOX and a sensitive drug release behavior at high glutathione (GSH) concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models. Results: TRRP has a high loading capacity of DOX and a sensitive drug release behavior at GSH concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models. Conclusions: This study demonstrated that TRRP was a promising therapeutic agent for enhancing TACE therapy for HCC treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Giant salamander protein peptide is a peptide with rich functional properties. Giant salamander protein peptide KGEYNK (KK‐6) is a peptide with both antioxidant and anti‐inflammatory properties. The antioxidant and anti‐inflammatory mechanisms of KK‐6 are still unclear. When we studied the functional mechanism of KK‐6, we found that the antioxidant property of KK‐6 has a synergistic and promoting effect on anti‐inflammatory properties. RESULTS: KK‐6 enhances cellular resistance to LPS via the MAPK/NF‐κB signaling pathway, leading to increased levels of inflammatory factors: interleukin‐1β (764.81 ng mL−1), interleukin‐6 (1.06 ng mL−1) and tumor necrosis factor‐α (4440.45 ng mL−1). KK‐6 demonstrates potent antioxidant properties by activating the Nrf2 signaling pathway, resulting in elevated levels of antioxidant enzymes (glutathione peroxidase: 0.03 μg mL−1; superoxide dismutase: 0.589 μg mL−1) and a reduction in the concentration of the oxidative product malondialdehyde (967.05 μg mL−1). CONCLUSION: Our findings highlight the great potential of KK‐6, a peptide extracted from giant salamander protein, as a remedy for intestinal inflammation. Through its dual role as an antioxidant and anti‐inflammatory agent, KK‐6 offers a promising avenue for alleviating inflammation‐related damage and oxidative stress. This study lays the foundation for further exploration of giant salamander products and highlights their importance in health and novel food development. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

INTRODUCTION: As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease‐modifying potential. They are therefore currently being designed and target either the 306VQIVYK311 aggregation‐promoting hotspot found in all Tau isoforms or the 275VQIINK280 aggregation‐promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood‐brain barrier, and rescue aggregation‐dependent Tau phenotypes in vivo. METHODS: We developed a retro‐inverso, stable D‐amino peptide, RI‐AG03 [Ac‐rrrrrrrrGpkyk(ac)iqvGr‐NH2], based on the 306VQIVYK311 hotspots which exhibit these disease‐relevant attributes. RESULTS: Unlike other aggregation inhibitors, RI‐AG03 effectively suppresses aggregation of multiple Tau species containing both hotspots in vitro and in vivo, is non‐toxic, and suppresses aggregation‐dependent neurodegenerative and behavioral phenotypes. DISCUSSION: RI‐AG03 therefore meets many clinically relevant requirements for an anti‐aggregation Tau therapeutic and should be explored further for its disease‐modifying potential for Tauopathies. Highlights: Our manuscript describes the development of a novel peptide inhibitor of Tau aggregation, a retro‐inverso, stable D‐amino peptide called RI‐AG03 that displays many clinically relevant attributes. We show its efficacy in preventing Tau aggregation in both in vitro and in vivo experimental models while being non‐toxic to cells. RI‐AG03 also rescues a biosensor cell line that stably expresses Tau repeat domains with the P301S mutation fused to Cer/Clo and rescues aggregation‐dependent phenotypes in vivo, suppressing neurodegeneration and extending lifespan.Collectively our data describe several properties and attributes of RI‐AG03 that make it a promising disease‐modifying candidate to explore for reducing pathogenic Tau aggregation in Tauopathies such as Alzheimer's disease. Given the real interest in reducing Tau aggregation and the potential clinical benefit of using such agents in clinical practice, RI‐AG03 should be investigated further for the treatment of Tauopathies after validation in mammalian models.Tau aggregation inhibitors are the obvious first choice as Tau‐based therapies as much of Tau‐mediated toxicity is aggregation dependent. Indeed, there are many research efforts focusing on this therapeutic strategy with aggregation inhibitors being designed against one of the two aggregation‐promoting hotspots of the Tau protein. To our knowledge, RI‐AG03 is the only peptide aggregation inhibitor that inhibits aggregation of Tau by targeting both aggregation‐promoting hotspot motifs simultaneously. As such, we believe that our study will have a significant impact on drug discovery efforts in this arena. [ABSTRACT FROM AUTHOR]

Population aging, reduced economic capacity, and neglecting the treatments for oral pathologies, are the main causal factors for about 3 billion individuals who are suffering from partial/total edentulism or alveolar bone resorption: thus, the demand for dental implants is increasingly growing. To achieve a good prognosis for implant‐supported restorations, adequate peri‐implant bone volume is mandatory. The Guided Bone Regeneration (GBR) technique is one of the most applied methods for alveolar bone reconstruction and treatment of peri‐implant bone deficiencies. This technique involves the use of different types of membranes in association with some bone substitutes (autologous, homologous, or heterologous). However, time for bone regeneration is often too long and the bone quality is not simply predictable. This study aims at engineering and evaluating the efficacy of modified barrier membranes, enhancing their bioactivity for improved alveolar bone tissue regeneration. We investigated membranes functionalized with chitosan (CS) and chitosan combined with the peptide GBMP1α (CS + GBMP1α), to improve bone growth. OsseoGuard® membranes, derived from bovine Achilles tendon type I collagen crosslinked with formaldehyde, were modified using CS and CS + GBMP1α. The functionalization, carried out with 1‐ethyl‐3‐(3 dimethylaminopropyl)carbodiimide and sulfo‐N‐Hydroxysuccinimide (EDC/sulfo‐NHS), was assessed through FT‐IR and XPS analyses. Biological assays were performed by directly seeding human osteoblasts onto the materials to assess cell proliferation, mineralization, gene expression of Secreted Phosphoprotein 1 (SPP1) and Runt‐Related Transcription Factor 2 (Runx2), and antibacterial properties. Both CS and CS + GBMP1α functionalizations significantly enhanced human osteoblast proliferation, mineralization, gene expression, and antibacterial activity compared to commercial membranes. The CS + GBMP1α functionalization exhibited superior outcomes in all biological assays. Mechanical tests showed no significant alterations of membrane biomechanical properties post‐functionalization. The engineered membranes, especially those functionalized with CS + GBMP1α, are suitable for GBR applications thanks to their ability to enhance osteoblast activity and promote bone tissue regeneration. These findings suggest a potential advancement in the treatment of oral cavity problems requiring bone regeneration. [ABSTRACT FROM AUTHOR]

Self‐assembled peptides are used for diverse applications in the biomedical and technological fields. The morphology and function of the assembled systems are dictated by the peptide sequence and length. In this work, a supramolecular catalyst was obtained upon self‐assembly of the diphenylalanine peptide conjugated to a triphenylphosphine Au(I) complex in acetonitrile. The assembled molecules were characterized by spectroscopic techniques and by scanning electron microscopy. The activity of the catalyst was tested on two substrates in cyclization reactions. The morphology and the dimensions of the assembled systems vary depending on the presence of a carboxyl versus an amide C‐terminal end. The catalyst efficiently promotes intramolecular cyclization reactions. Results obtained encourage the use of self‐assembled peptides for the obtainment of new and efficient catalysts. [ABSTRACT FROM AUTHOR]

Bioactive peptides play crucial roles in the biomedicine fields including cancer therapy and regenerative medicine due to their favorable biocompatibility, low immunogenicity, and excellent biological activity. However, their low stability greatly limits their clinical application. Herein, a novel bioactive peptide delivery strategy is reported that utilizes triphen[3]arene polyvalent‐conjugated bioactive peptides to induce self‐assembly and form nanofibers to enhance the in vivo stability and bioactivity of bioactive peptides. Specifically, a water‐soluble triphen[3]arene (WTP3(YRSRK)6, Comp. 2) containing six FGF‐mimicking peptides, primarily comprising two components: triphen[3]arene serves as a skeleton molecule and an assembly motif with multiple customizable sites, while YRSRK is a pentapeptide with fibroblast growth factor 2 (FGF‐2) biological activity. Despite the presence of the inhibitor dexamethasone (Dex), Comp. 2 continued to enhance cell proliferation by 15% and rescued 17% of cells from apoptosis. The administration of Comp. 2 resulted in improved restoration of skeletal muscle atrophy and functional damage in mice. The mean grip strength increased by 42%, and the calf muscle volume increased by 17%. This innovative approach of utilizing macrocycle polyvalent conjugated bioactive peptides offers a universal method for enabling bioactive peptides to produce sustained and efficient biological effects, potentially advancing the development of promising peptide‐based nanomedicines. [ABSTRACT FROM AUTHOR]

Background: In recent years, the interest in Al[18F]F as a labeling agent for Positron Emission Tomography (PET) radiotracers has risen, as it allows for fast and efficient fluorine-18 labeling by harnessing chelation chemistry. The introduction of Restrained Complexing Agent (RESCA) as a chelator has also shown that chelator-based radiolabeling reactions can be performed in mild conditions, making the radiolabeling process attractively more facile than most conventional radiofluorination methods. The aim of the study was to establish optimized conditions for Al[18F]F labeling of Affibody molecules using RESCA as a complexing agent, using Z09591 and Z0185, two Affibody proteins targeting PDGFRβ and TNFα, respectively, as model compounds. Results: The Al[18F]F labeling of RESCA-conjugated Z09591 was tested at different temperatures (rt to 60 °C) and with varying reaction times (12 to 60 min), and optimal conditions were then implemented on RESCA-Z0185. The optimized synthesis method was: 1.5–2.5 GBq of cyclotron produced fluorine-18 were trapped on a QMA cartridge and eluted with saline solution to react with 12 nmol of AlCl3 and form Al[18F]F. The respective RESCA-conjugated Affibody molecule (14 nmol) in NaOAc solution was added to the Al[18F]F solution and left to react at 60 °C for 12 min. The mixture was purified on a NAP5 size exclusion column and then analyzed by HPLC. The entire process took approximately 35 min, was highly reproducible, indicating the efficiency and reliability of the method. The labeled compounds demonstrated retained biological function for their respective targets after purification. Conclusions: We present a general and optimized method for Al[18F]F labeling of RESCA-conjugated Affibody molecules, which can be widely applied to this class of peptide-based imaging agents. Moreover, radiochemical yields were improved when the labeling was conducted at 37 °C or above. In vitro and in vivo assessment of the respective tracers was promising, showing retained binding capacity as well as moderate defluorination, which is usually regarded as a potential downside for RESCA-conjugated tracers. [ABSTRACT FROM AUTHOR]

Opioid use disorder ‐ particularly involving fentanyl ‐ has precipitated a public health crisis characterized by a significant increase in addiction and overdose‐related deaths. Fentanyl‐specific immunotherapy, which aims at inducing fentanyl‐specific antibodies capable of binding fentanyl molecules in the bloodstream, preventing their entry in the central nervous system, is therefore gaining momentum. Conventional opioid designs rely on the covalent conjugation of fentanyl analogues to immunogenic carrier proteins that hold the inherent capacity of mounting immunodominant responses. Here, we present an alternative fentanyl vaccine design that utilizes a non‐covalent assembly of lipid nanoparticles (LNPs) to deliver fentanyl haptens in conjunction with a CD4+ T‐helper peptide epitope and an imidazoquinoline TLR7/8 agonist. Our results demonstrate that a single intramuscular administration of the LNP‐based nanovaccine elicits fentanyl‐specific antibodies, significantly mitigating the effects of opioid overdose in preclinical mouse models. Furthermore, we analyzed the immunobiological behavior of the vaccine in vivo in mouse models, providing evidence that covalent attachment of a fentanyl hapten to a carrier proteins or peptide epitope is not necessary for inducing an effective immune response. However, co‐delivery ‐ specifically, the physical assembly of all immune cues into an LNP ‐ remains essential for inducing hapten‐specific immunity. [ABSTRACT FROM AUTHOR]

Metal binding to β‐sheets occurs in many metalloproteins and is also implicated in the pathology of Alzheimer's disease. De novo designed metallo‐β‐sheets have been pursued as models and mimics of these proteins. However, no crystal structures of canonical β‐sheet metallopeptides have yet been obtained, in stark contrast to many examples for ɑ‐helical metallopeptides, leading to a poor understanding for their chemistry. To address this, we have engineered tryptophan zippers, stable 12‐residue β‐sheet peptides, to bind Cu(II) ions and obtained crystal structures through single crystal X‐ray diffraction (SC‐XRD). We find that metal binding triggers several unexpected supramolecular assemblies that demonstrate the range of higher‐order structures available to metallo‐β‐sheets. Overall, these findings underscore the importance of crystallography in elucidating the rich structural landscape of metallo‐β‐sheet peptides. [ABSTRACT FROM AUTHOR]

Introduction: Melittin is a potent antimicrobial peptide from bee venom that is effective against both Gram-positive and Gram-negative bacteria. However, it is extremely toxic to mammalian cells and, as yet, has no clinical use. Modifications to its amino acid sequence, cyclization, truncation, and dimerization have been attempted in order to reduce its toxicity whilst maintaining its antimicrobial activity. Methods: In this study, we targeted the three lysine residues present in melittin and substituted them with lysine homologs containing shorter side chains (ornithine, Orn, diaminobutyric acid, Dab, and diaminopropanoic acid, Dap) and made both parallel and antiparallel melittin dimers to observe how lysine substitution and dimerization affects its activity and toxicity. The antibacterial activity of melittin and its analogs was tested against S. aureus (Gram-positive bacteria) and E. coli (Gram-negative bacteria), and cytotoxicity was tested against the mammalian cell lines HEK293 and H4IIE. Results: Overall, dimerization and lysine substitution exhibited improved antimicrobial activity toward E. coli and limited improvement toward S. aureus. However, mammalian cell toxicity was only marginally reduced compared to native melittin. Interestingly, the parallel dimer was found to be marginally more active than the antiparallel dimer, indicating orientation maybe important for activity, although both dimers were less effective than the native and Lys-analog peptides toward S. aureus. Of the Lys substitutions, Dab and Dap improved melittin's activity toward E. coli. Discussion: Dimerization and Lys substitution of melittin improved the antimicrobial activity toward Gram-negative bacteria but did not significantly improve its activity toward Gram-positive bacteria. Some analogs also displayed reduced toxicity toward HEK293 and H4IIE cells but overall remained toxic at bactericidal concentrations. Our data indicates that although highly antibacterial, melittin's toxicity is the major drawback in its potential use. [ABSTRACT FROM AUTHOR]

With exceptional photochromic and photoluminescent properties, spiropyrans have demonstrated significant potential for advanced information encryption and anti‐counterfeiting applications. However, its inherent water insolubility leads to incompatibility with aqueous polymers, and even more, its ease of leaching from the matrix hinders the formation of stable stimuli‐responsive platforms through direct blending with all polymers. Here, the fabrication of amphiphilic spiropyran‐octapeptide molecules is reported that can spontaneously self‐assemble into highly water‐dispersible supramolecular nanofibers in water. These assemblies exhibit universal polymer matrix compatibility while retaining the rapid photo‐responsiveness of spiropyrans. The formation of strong interactions between the supramolecular assembly and polymer chains ensures the long‐term stability of the resultant stimuli‐responsive materials in aqueous environments. These platforms fully preserve the base polymers’ processing properties, with silk fibroin as the matrix offering exceptional opportunities for constructing photo‐responsive platforms in various forms (e.g., films, gels, fibers, and coatings) with multiple functionalities using diverse solution processing techniques. Integrating distinct photochromic and photoluminescent responses within a single format without interference, combined with environmental stability and processing flexibility, enables the creation of dual‐mode, high‐security encryption devices for diverse application scenarios. The outlined strategy provides innovative concepts for developing high‐performance, versatile intelligent systems utilizing stimulus‐responsive molecules. [ABSTRACT FROM AUTHOR]

A synthesis of acyl halides from the corresponding carboxylic acid thioesters was achieved using commercially available Selectfluor or NCS, and the acyl fluoride or chloride intermediates were transformed to the corresponding esters, amides, and several carbon‐carbon bond formation products. This approach can be applied to the peptide synthesis from functionalized amino acid thioesters. [ABSTRACT FROM AUTHOR]

While remarkable progress has been made in the development of peptide medicines, many problems related to peptide synthesis remain unresolved. Previously, we reported electrochemical peptide synthesis using a phosphine as a potentially recyclable coupling reagent. However, there was room for improvement from the point of view of reaction efficiency, especially in the carboxylic acid activation step and the peptide bond formation step. To overcome these challenges, we searched for the optimal phosphine. Among phosphines with various electronic properties, we found that electron‐rich triaryl phosphines improved the reaction efficiency. Consequently, we successfully performed electrochemical peptide synthesis on sterically hindered and valuable amino acids. We also synthesized oligopeptides that were challenging with our previous method. Finally, we examined the effect of substituents on the phosphine cations, and gained some insights into reactivity, which will aid researchers designing reactions involving phosphine cations. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The main purpose of this study is to predict the effect of Tyr-Lys-Thr (YKT) tripeptide, recognized for its anticancer properties, on lung cancer through theoretical and experimental analyzes. BACKGROUND: Peptides are important therapeutic compounds that have been studied for many years. Among these, YKT tripeptide emerges as a significant therapeutic peptide, exhibiting cytotoxic effects on various cancer cell lines. METHODS: The study investigated the involvement of the PI3K/Akt/mTOR pathway, commonly activated in human cancer, and the pivotal role of caspases in apoptosis. The interactions of YKT tripeptide with mTOR, Akt, PI3K, caspase-3, and caspase-8 were investigated through the molecular docking method. Additionally, MTT test was used to determine the cytotoxic activity of YKT against the A549 cell line across concentrations set at 0.1, 0.25, 0.5, 1, 2.5 and 5 mg/mL for 24 and 48 h. RESULTS AND CONCLUSION: In silico docking studies were conducted with PI3K, Akt1, and mTOR, known to be active in human cancer, as well as caspase-3 and caspase-8, key enzymes in apoptosis. It was determined that YKT exhibited a robust binding tendency with each receptor. YKT tripeptide was also found to have a cytotoxic effect on human lung carcinoma cell line A549 [ABSTRACT FROM AUTHOR]

Simple Summary: Subunit vaccines based on peptides as minimal immunogenic epitopes/antigens can induce highly specific immune responses without triggering adverse reactions. Here, Salmonella enterica serovar Typhimurium peptides were identified in the immunopeptidome of porcine macrophages genotyped for different class II molecules that were stimulated with the bacteria. Immunopeptidomics and mass spectrometry approaches were used for peptide identification, along with two predictors for immunoinformatics analysis. Differences between individuals were observed concerning length, elution preferences, and elution predictions. Thirty-one bacterial peptides were identified; outer membrane protein-A and chaperonin GroEL protein had the highest number of peptides. Since proteins having the highest number of peptides have been suggested as candidate antigens for vaccines, all the bacterial peptides identified can be considered promising candidate epitopes upon determining their immunogenicity. Salmonellosis is a zoonotic infection that has a major impact on human health; consuming contaminated pork products is the main source of such infection. Vaccination responses to classic vaccines have been unsatisfactory; that is why peptide subunit-based vaccines represent an excellent alternative. Immunopeptidomics was used in this study as a novel approach for identifying antigens coupled to major histocompatibility complex class II molecules. Three homozygous individuals having three different haplotypes (Lr-0.23, Lr-0.12, and Lr-0.21) were thus selected as donors; peripheral blood macrophages were then obtained and stimulated with Salmonella typhimurium (MOI 1:40). Although similarities were observed regarding peptide length distribution, elution patterns varied between individuals; in total, 1990 unique peptides were identified as follows: 372 for Pig 1 (Lr-0.23), 438 for Pig 2 (Lr.0.12) and 1180 for Pig 3 (Lr.0.21). Thirty-one S. typhimurium unique peptides were identified; most of the identified peptides belonged to outer membrane protein A and chaperonin GroEL. Notably, 87% of the identified bacterial peptides were predicted in silico to be elution ligands. These results encourage further in vivo studies to assess the immunogenicity of the identified peptides, as well as their usefulness as possible protective vaccine candidates. [ABSTRACT FROM AUTHOR]

This study explores the potential of natural bioactive peptides from animal venoms as targeted anti-cancer agents with reduced toxicity. Initially, we screened a broad collection of animal venoms for their antiproliferative activity against cancer cell lines. From this collection, we selected venoms from Naja anchietae and Naja senegalensis due to their promising activity. Utilizing reverse- phase high-performance liquid chromatography (RP HPLC), mass spectrometry (MALDI-TOF MS and MALDI-TOF TOF MSMS), and Edman degradation sequencing, we isolated and characterized three peptides named CTNanc1, CTNanc2, and CTNanc3 from Naja anchietae, and three others named CTNsen1, CTNsen2, and CTNsen3 from Naja senegalensis, each with a molecular weight of around 7 kDa. These purified peptides demonstrated inhibition of U87 glioblastoma cell proliferation, but not of U251 and T98G cells, in cell viability assays. To assess the impact of these treatments on cell viability, apoptosis, and necrosis, flow cytometry assays were conducted on U87 cells at 72 h. The results showed a decrease in cell viability and an increase in dead cells, suggesting that the treatments not only promote apoptosis, but may also lead to increased necrosis or late-stage apoptosis as the exposure time increases. These findings suggest that these peptides could be developed as leads for cancer therapy. [ABSTRACT FROM AUTHOR]

Systemin, the first peptide hormone identified in plants, was initially isolated from tomato (Solanum lycopersicum) leaves. Systemin mediates local and systemic wound‐induced defense responses in plants, conferring resistance to necrotrophic fungi and herbivorous insects. Systemin is recognized by the leucine‐rich‐repeat receptor‐like kinase (LRR‐RLK) receptor SYSTEMIN RECEPTOR1 (SYR1), but how the systemin recognition signal is transduced to intracellular signaling pathways to trigger defense responses is poorly understood. Here, we demonstrate that SERK family LRR‐RLKs function as co‐receptors for SYR1 to mediate systemin signal transduction in tomato. By using chemical genetic approaches coupled with engineered receptors, we revealed that the association of the cytoplasmic kinase domains of SYR1 with SERKs leads to their mutual trans‐phosphorylation and the activation of SYR1, which in turn induces a wide range of defense responses. Systemin stimulates the association between SYR1 and all tomato SERKs (SlSERK1, SlSERK3A, and SlSERK3B). The resulting SYR1‐SlSERK heteromeric complexes trigger the phosphorylation of TOMATO PROTEIN KINASE 1B (TPK1b), a receptor‐like cytoplasmic kinase that positively regulates systemin responses. Additionally, upon association with SYR1, SlSERKs are cleaved by the Pseudomonas syringae effector HopB1, further supporting the finding that SlSERKs are activated by systemin‐bound SYR1. Finally, genetic analysis using Slserk mutants showed that SlSERKs are essential for systemin‐mediated defense responses. Collectively, these findings demonstrate that the systemin‐mediated association of SYR1 and SlSERKs activates defense responses against herbivorous insects. [ABSTRACT FROM AUTHOR]

The skin is an essential organ that protects the body from external aggressions; therefore, damage from various wounds can significantly impair its function, and effective methods for regenerating and restoring its barrier function are crucial. This study aimed to mass-produce wound-healing exosomes using a fragment of the fibroblast growth factor 2 (FGF2)-derived peptide (FP2) to enhance cell proliferation and exosome production. Our experiments demonstrated increased cell proliferation when Wharton's jelly mesenchymal stem cells (WJ MSCs) were coated with FP2. Exosomes from FP2-coated WJ MSCs were analyzed using nanoparticle-tracking analysis, transmission electron microscopy, and Western blotting. Subsequently, fibroblasts were treated with these exosomes, and their viability and migration effects were compared. Anti-inflammatory effects were also evaluated by inducing pro-inflammatory factors in RAW264.7 cells. The treatment of fibroblasts with FP2-coated WJ MSC-derived exosomes (FP2-exo) increased the expression of FGF2, confirming their wound-healing effect in vivo. Overall, the results of this study highlight the significant impact of FP2 on the proliferation of WJ MSCs and the anti-inflammatory and wound-healing effects of exosomes, suggesting potential applications beyond wound healing. [ABSTRACT FROM AUTHOR]

A peptide's fractional mass is directly associated with its elemental composition and thus amino acid composition. Here it is demonstrated that a peptide's fractional mass alone can be a useful identifier or indicator of that composition for small to mid‐sized peptides (5–7 amino acids) and can significantly reduce the number of viable amino acid compositions for larger peptides (> 8 residues) to include or exclude certain possibilities. Separate consideration of the integer portion of the peptide's mass helps to reduce the number of possibilities where many duplicate fractional mass values are found. Adoption of this fractional mass strategy should aid approaches that are presently employed for peptide identification, including in the use of mass map data to search protein databases for proteomics applications. [ABSTRACT FROM AUTHOR]

Microglia are immune‐derived cells critical to the development and healthy function of the brain and spinal cord, yet are implicated in the active pathology of many neuropsychiatric disorders. A range of functional phenotypes associated with the healthy brain or disease states has been suggested from in vivo work and were modeled in vitro as surveying, reactive, and primed sub‐types of primary rat microglia and mixed microglia/astrocytes. It was hypothesized that the biomolecular profile of these cells undergoes a phenotypical change as well, and these functional phenotypes were explored for potential novel peptide binders using a custom 7 amino acid‐presenting M13 phage library (SX7) to identify unique peptides that bind differentially to these respective cell types. Surveying glia were untreated, reactive were induced with a lipopolysaccharide treatment, recovery was modeled with a potent anti‐inflammatory treatment dexamethasone, and priming was determined by subsequently challenging the cells with interferon gamma. Microglial function was profiled by determining the secretion of cytokines and nitric oxide, and expression of inducible nitric oxide synthase. After incubation with the SX7 phage library, populations of SX7‐positive microglia and/or astrocytes were collected using fluorescence‐activated cell sorting, SX7 phage was amplified in Escherichia coli culture, and phage DNA was sequenced via next‐generation sequencing. Binding validation was done with synthesized peptides via in‐cell westerns. Fifty‐eight unique peptides were discovered, and their potential functions were assessed using a basic local alignment search tool. Peptides potentially originated from proteins ranging in function from a variety of supportive glial roles, including synapse support and pruning, to inflammatory incitement including cytokine and interleukin activation, and potential regulation in neurodegenerative and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Peptides are native binders involved in numerous physiological life procedures, such as cellular signaling, and serve as ready-made regulators of biochemical processes. Meanwhile, small molecules compose many drugs owing to their outstanding advantages of physiochemical properties and synthetic convenience. A novel field of research is converting peptides into small molecules, providing a convenient portable solution for drug design or peptidomic research. Endowing properties of peptides onto small molecules can evolutionarily combine the advantages of both moieties and improve the biological druggability of molecules. Herein, we present eight representative recent cases in this conversion and elaborate on the transformation process of each case. We discuss the innovative technological methods and research approaches involved, and analyze the applicability conditions of the approaches and methods in each case, guiding further modifications of peptides to small molecules. Finally, based on the aforementioned cases, we summarize a general procedure for peptide-to-small molecule modifications, listing the technological methods available for each transformation step and providing our insights on the applicable scenarios for these methods. This review aims to present the progress of peptide-to-small molecule modifications and propose our thoughts and perspectives for future research in this field. This review outlines the transformation of peptides into small molecules, highlighting classical and innovative methods contributing in four stages, providing insights and perspectives for future research in novel drug design. [Display omitted] [ABSTRACT FROM AUTHOR]

Tissue engineering presents a promising approach for the treatment of meniscal injuries, yet the development of meniscal scaffolds that exhibit both superior biomechanical properties and biocompatibility remains a considerable challenge. In this study, decellularized skin matrix (DSM) scaffolds were first prepared using porcine skin through decellularization and freeze-drying techniques. The DSM scaffold has favorable porosity, hydrophilicity, and biocompatibility. Importantly, the collagen content and tensile modulus of the scaffold are comparable to those of native meniscus (44.13 ± 2.396 mg/g vs. 42.41 ± 2.40 mg/g and 103.30 ± 2.98 MPa vs. 128.80 ± 9.115 MPa). Subsequently, the peptide PFSSTKT (PFS) with mesenchymal stem cells (MSCs) recruitment capability was used to modify DSM to construct DSM-PFS scaffolds. Compared to the DSM scaffold, the optimized DSM-PFS scaffold enhanced in vitro collagen and glycosaminoglycan (GAG) production and upregulated the expression of cartilage-specific genes. Furthermore, the DSM-PFS scaffold was more effective in recruiting MSCs in vitro. In vivo studies in rabbit models showed that the DSM-PFS scaffold successfully promoted meniscus tissue regeneration. Three months post-implantation, meniscus tissue formation can be observable, and after six months, the neo-meniscus exhibited tissue structure and tensile properties similar to the native meniscus. Notably, the DSM-PFS scaffold exhibited significant chondroprotective effects, slowing osteoarthritis (OA) progression. In conclusion, the DSM-PFS scaffold may represent a promising candidate for future applications in meniscus tissue engineering. We developed a decellularized skin matrix (DSM) meniscus scaffold using whole-layer porcine skin, demonstrating superior biomechanical strength and biocompatibility. Following modification with the stem cell-recruiting peptide PFS, the optimized DSM-PFS scaffold outperformed the DSM scaffold in cell attraction, collagen and glycosaminoglycan production, and cartilage-specific gene expression. Implanted into rabbit knee joints, the cell-free DSM-PFS scaffold induced meniscal tissue formation within three months, achieving the histological structure and tensile strength of the native meniscus by six months. Moreover, it significantly protected the cartilage. Our findings provide new insights into the fabrication of scaffolds for meniscal tissue engineering, with the DSM-PFS scaffold emerging as an ideal candidate for future applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Breast cancer remains a leading cause of morbidity and mortality among women worldwide, emphasizing the urgent need for enhanced diagnostic and therapeutic approaches. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) has emerged as a notable target due to its markedly elevated expression in breast tumors, suggesting the viability of LRG1 as a theranostic target. In our study, we employed phage display technology to identify a peptide, termed ET, that binds to LRG1 with a dissociation constant of 48.4 µM. After modified with fluorescent cyanine dye, the ET peptide showcased effective tumor-targeting imaging across three different primary breast tumor models and a metastatic breast tumor model. We also undertook a comprehensive safety evaluation, which verified the good biosafety credentials of ET peptide. In summary, the ET peptide identified in this study shows effective LRG1-targeting ability both in vitro and in vivo, thus exhibiting immense potential for clinical translation. [ABSTRACT FROM AUTHOR]

In this study, we successfully isolated Bacillus strains with high protease activity from deep-sea mineral water in Korea and used them to obtain functional peptide fractions from chia seeds. The obtained Bacillus strains showed a high similarity of 99% with B. altitude with a long rod type (named B. altitudinis 5-DSW) and high protease activity at 40 °C, and 70% of the activity remained even at 70 °C. The defatted chia seed protein (15–50 kDa) was treated with crude protease from B. altitudinis 5-DSW and digested into small peptides below 20 kDa. The obtained chia seed peptides showed 3 times and 1.5 times higher antioxidant activity in DPPH and ABT radical scavenging assays, respectively. Moreover, chia seed peptides showed enhanced AChE inhibitory activity with an IC50 value of 14.48 ± 0.88 μg/mL and BChE inhibition activity with an IC50 value of 10.90 ± 0.80 μg/mL. Our results indicate that the newly isolated B. altitudinis 5-DSW and chia seed protein hydrolysates have potential applications in biotechnology and functional food development, enhancing the nutritional quality and value-added utilization of chia byproducts. [ABSTRACT FROM AUTHOR]

Short sequences of amino acids called peptides have a wide range of biological functions and the potential to treat a number of diseases. Bioactive peptides can be derived from different sources, including marine organisms, and synthetic design, making them versatile candidates for production of therapeutic agents. Their therapeutic effects span across areas such as antimicrobial activity, cells proliferation and migration, synthesis of collagen, and more. This current review explores the fascinating realm of bioactive peptides as promising therapeutic agents for skin wound healing. This review focuses on the multifaceted biological effects of specific peptides, shedding light on their potential to revolutionize the field of dermatology and regenerative medicine. It delves into how these peptides stimulate collagen synthesis, inhibit inflammation, and accelerate tissue regeneration, ultimately contributing to the effective repair of skin wounds. The findings underscore the significant role several types of bioactive peptides can play in enhancing wound healing processes and offer promising insights for improving the quality of life for individuals with skin injuries and dermatological conditions. The versatility of peptides allows for the development of tailored treatments catering to specific wound types and patient needs. As continuing to delve deeper into the realm of bioactive peptides, there is immense potential for further exploration and innovation. Future endeavors may involve the optimization of peptide formulations, elucidation of underlying molecular and cellular mechanisms. [ABSTRACT FROM AUTHOR]

Calcium phosphates (CaPs) and their substituted derivatives encompass a large number of compounds with a vast presence in nature that have aroused a great interest for decades. In particular, hydroxyapatite (HAp, Ca10(OH)2(PO4)6) is the most abundant CaP mineral and is significant in the biological world, at least in part due to being a major compound in bones and teeth. HAp exhibits excellent properties, such as safety, stability, hardness, biocompatibility, and osteoconductivity, among others. Even some of its drawbacks, such as its fragility, can be redirected thanks to another essential feature: its great versatility. This is based on the compound's tendency to undergo substitutions of its constituent ions and to incorporate or anchor new molecules on its surface and pores. Thus, its affinity for biomolecules makes it an optimal compound for multiple applications, mainly, but not only, in biological and biomedical fields. The present review provides a chemical and structural context to explain the affinity of HAp for biomolecules such as proteins and nucleic acids to generate hybrid materials. A size-dependent criterium of increasing complexity is applied, ranging from amino acids/nucleobases to the corresponding macromolecules. The incorporation of metal ions or metal complexes into these functionalized compounds is also discussed. [ABSTRACT FROM AUTHOR]

Conformational freedom-restricted peptides, such as stapled peptides, play a crucial role in the advancement of functional peptide development. We synthesized stapled octapeptides using α-carbocyclic α,α-disubstituted α-amino acids, particularly 3-allyloxy-1-aminocyclopentane-1-carboxylic acid, as the crosslink motifs. The organocatalytic capabilities of the synthesized stapled peptides were assessed in an asymmetric nucleophilic epoxidation reaction because the catalytic activities are known to be proportional to α-helicity. Despite incorporating side-chain crosslinks, the enantioselectivities of the epoxidation reaction catalyzed by stapled octapeptides were found to be comparable to those obtained using unstapled peptides. Interestingly, the stapled peptides using α-carbocyclic α,α-disubstituted α-amino acids demonstrated higher reactivities and stereoselectivities (up to 99% ee) compared to stapled peptides derived from (S)-α-(4-pentenyl)alanine, a commonly used motif for stapled peptides. These differences could be attributed to the increased α-helicity of the former stapled peptide in contrast to the latter, as evidenced by the X-ray crystallographic structures of their N-tert-butoxycarbonyl derivatives. [ABSTRACT FROM AUTHOR]

AbstractThe venom of the Odontobuthus doriae scorpion, prevalent in East Asia and Iran, has not been fully characterized. This study provides the first proteomic profile of O. doriae venom to explore its potential as a medical. 2D-PAGE analysis revealed 96 protein spots with isoelectric points from 3 to 9 and molecular weights between 6.6 to 205 kDa. Fourteen toxin fractions were isolated via HPLC, and SDS-PAGE showed seven protein bands ranging from 3.8 to 182 kDa. MALDI-TOF MS identified Peptide 1 and Peptide 2, resembling Hemoglobin beta-2 chain and Chaperonin HSP60 and suggest potential therapeutic applications for P1 and P2. [ABSTRACT FROM AUTHOR]

The bioactive peptides derived from yak milk cheese exhibited cholesterol-lowering properties. However, there was limited research on their inhibitory effects on cholesterol esterase (CE) and elucidation of their potential inhibitory mechanisms. In this study, we identified CE-inhibiting peptides through virtual screening and in vitro assays. Additionally, molecular docking and molecular dynamics studies were conducted to explore the mechanisms. The results indicated that peptides RK7 (RPKHPIK), KQ7 (KVLPVPQ), QP13 (QEPVLGPVRGPFP), TL9 (TPVVVPPFL), VN10 (VYPFPGPIPN), LQ10 (LPPTVMFPPQ), and SN12 (SLVYPFPGPIPN) possessed molecular weights of less than 1.5 kDa and a high proportion of hydrophobic amino acids, demonstrating notable inhibitory effects on CE. Molecular docking and dynamics revealed that peptides RK7, KQ7, QP13, and VN10 bound to key amino acid residues Arg423, His435, and Ser422 of CE through hydrogen bonds, hydrophobic interactions, salt bridges, and π–π stacking, occupying the substrate-binding site and exerting inhibitory effects on CE. The four peptides were further synthesized to verify their CE-inhibitory effects in vitro. RK7, KQ7, QP13, and VN10 exhibited inhibitory activity on CE with IC50 values of 8.16 × 10−7 mol/L, 8.10 × 10−7 mol/L, 4.63 × 10−7 mol/L, and 7.97 × 10−7 mol/L; RK7, KQ7, QP13, and VN10 were effective in inhibiting CE after simulated gastrointestinal digestion, especially with a significant increase in the inhibitory activity of KQ7 and RK7, respectively. Our findings suggested that bioactive peptides from yak milk cheese represented a novel class of potential CE inhibitors. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress, a condition characterized by excessive production of reactive oxygen species (ROS), can cause significant damage to cellular macromolecules, leading to neurodegeneration. This underscores the need for effective antioxidant therapies that can mitigate oxidative stress and its associated neurodegenerative effects. KC14 peptide derived from liver-expressed antimicrobial peptide-2 A (LEAP 2 A) from Cyprinus carpio L. has been identified as a potential therapeutic agent. This study focuses on the antioxidant and neuroprotective properties of the KC14 peptide is to evaluate its effectiveness against oxidative stress and neurodegeneration. Methods: The antioxidant capabilities of KC14 were initially assessed through in silico docking studies, which predicted its potential to interact with oxidative stress-related targets. Subsequently, the peptide was tested at concentrations ranging from 5 to 45 µM in both in vitro and in vivo experiments. In vivo studies involved treating H2O2-induced zebrafish larvae with KC14 peptide to analyze its effects on oxidative stress and neuroprotection. Results: KC14 peptide showed a protective effect against the developmental malformations caused by H2O2 stress, restored antioxidant enzyme activity, reduced neuronal damage, and lowered lipid peroxidation and nitric oxide levels in H2O2-induced larvae. It enhanced acetylcholinesterase activity and significantly reduced intracellular ROS levels (p < 0.05) dose-dependently. Gene expression studies showed up-regulation of antioxidant genes with KC14 treatment under H2O2 stress. Conclusions: This study highlights the potent antioxidant activity of KC14 and its ability to confer neuroprotection against oxidative stress can provide a novel therapeutic agent for combating neurodegenerative diseases induced by oxidative stress. [ABSTRACT FROM AUTHOR]

Peptide‐based nanofibers are promising materials for many essential applications and can be generalized into two categories, self‐assembling peptide nanofibers (SAPNs) and poly(amino acid) nanofibers (PAANs). Non‐covalent SAPNs are sequence‐controllable, but poorly stable and not suitable for post‐modification. While covalent PAANs are post‐modifiable, however, their sequences are either monotonic or undefined. The nanofibers obtained by head‐to‐tail covalent coupling polymerization of sequence‐known peptides, which we call series‐connected peptide nanofibers (SCPNs), promise to have the advantages of both SAPNs and PAANs, but they are barely reported. The undesired backbiting effect during the head‐to‐tail polymerization is one of the possible challenges. Here, we present a template‐assisted strategy to trigger the flexible‐to‐rigid transition of peptide units, which can avoid the backbiting effect and enable consecutive intermolecular polymerization of peptides to produce desired sequence‐controlled covalent SCPNs. SCPNs are highly stable and can function as excellent parent materials for various post‐processing to create diverse hierarchical materials independent of the peptide sequence. Moreover, SCPNs allow for the display of predetermined functional groups at regular intervals along the nanofibers by pre‐modification of the initial peptide sequence. SCPNs represent a new category of peptide‐based nanofibers with outstanding performances and vast potential. [ABSTRACT FROM AUTHOR]

Amyloid‐β (Aβ) pathway is positioned as the center for Alzheimer's disease (AD) pathophysiology. Viable drugs targeting Aβ pathway are developed with promising outcomes. Meanwhile, most current approaches are focused on the inhibition of Aβ fibrillization or elimination of Aβ plaques by immunotherapeutic strategies. Here, near‐infrared (NIR) photothermal polypyrrole nanoparticles coated with peptide‐polyphenol are developed to both inhibit the Aβ fibrillization and disaggregate Aβ fibrils synergistically. Aβ fibrillization is obviously inhibited after being treated with the photothermal polypyrrole nanoparticles. Besides inhibition of Aβ fibrillization, the amount of Aβ fibrils is gradually reduced with time by 38.0% when co‐incubated with polypyrrole nanoparticles, indicating desired disaggregation capability against Aβ fibrils. In addition, faster and more disaggregation of Aβ fibrils is observed when irradiation by NIR light. Meanwhile, cellular studies also verified that this nanoparticle is able to effectively reduce the cytotoxicity of Aβ fibrils toward PC12 cells through disaggregating toxic Aβ aggregates and maintaining integral membrane structure. Hence, this peptide‐polyphenol‐coated NIR photothermal polypyrrole nanoparticle provides a new perspective for the inhibition of Aβ fibrillization and disaggregation of Aβ fibrils, which can serve as a promising approach for anti‐amyloidosis. [ABSTRACT FROM AUTHOR]

Here, we describe a new technology, designed to accelerate peptide discovery by quick identification and optimization of the residues critical for protein–protein interactions or ligand binding. We called it PepFusion. It is based on ligation of short DNA sequences generated from known ligand‐binding regions. We tested it by selecting peptide antagonists of interleukin‐6 (IL‐6), a key mediator of inflammatory diseases such as rheumatoid arthritis (RA), Crohn's disease, and Castleman disease (CD). The PepFusion library demonstrated superiority over a random library by yielding a peptide with low micromolar affinity for IL‐6, whereas the random library failed. The affinity of the peptide from the PepFusion library was further enhanced by additional rounds of mutagenesis leading to peptide variants with low nanomolar IL‐6 affinity. In addition to generating high‐affinity peptides, our method opens the way to solve the problem of the false positive sequences, which are common with all display technologies. [ABSTRACT FROM AUTHOR]

Gelatin and collagen are two animal-derived ingredients that are widely used in various industries. Both have distinctive physico-chemical characteristic that made them ingredients of interest for many industrial players to be applied as there are vast arrays of usage in the food, cosmetic and biomedical fields. However, the origin of gelatin and collagen poses ethical and religious concerns, especially for Muslims and Jews who have restrictions on food consumption. Porcine by-products are of concern for religious and health reasons, and there is a demand for precise and reliable detection techniques. The limitation of DNA detection is due to extreme environment in food processing which results in low extractability of DNA. Therefore, peptide-based detection using mass spectrometry is required. However, identify the suitable marker is like searching needle in haystacks. Hence, combination of bioinformatics and mass spectrometry is proposed. This study aims to identify the specific peptide biomarkers by employing bioinformatics technique which can be applied to identify gelatin and collagen sources with the aid of mass spectrometry. In these approach, combination of Petunia Trans-Proteomic Pipeline (TPP, version 5.2.0) and sequence alignment ClustalW were applied to facilitate the MS data (LC-QTOF-MS) and peptide identification. As a result, 69 fasta file of protein sequence from both UniProtKB and NCBInr have been collected, 81 collagen peptides sequence and 118 gelatine peptides has been attainable that have the potential to distinguish different species. In conclusion, in silico protein sequence approaches helps to enable rapid screening of proteotypic peptides that can serve as species biomarkers proficiently. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a significant public health issue. The unprecedented spread of antimicrobial-resistant organisms has been identified by the World Health Organization as one of the leading healthcare threats. Projections for annual worldwide deaths attributed to antimicrobial resistance approach 10 million by 2050, with an associated economic burden of USD 100 trillion. This paper reviews the mechanisms known to contribute to antimicrobial resistance and provides insight into potential available alternatives to conventional antibiotics. Antimicrobial approaches addressed include dual antibiotic therapy, antimicrobial peptides, monoclonal antibodies, bacteriophages, probiotics, nanomaterials, and cannabinoids. Key pathogens in need of antimicrobials referred to as the ESKAPE pathogens are discussed. [ABSTRACT FROM AUTHOR]

Enzymes play key roles in the biological functions of living organisms, which serve as catalysts to and regulate biochemical reaction pathways. Recent studies suggest that peptides are promising molecules for modulating enzyme function due to their advantages in large chemical diversity and well-established methods for library synthesis. Experimental approaches to identify protein-binding peptides are time-consuming and costly. Hence, there is a demand to develop a fast and accurate computational approach to tackle this problem. Another challenge in developing a computational approach is the lack of a large and reliable dataset. In this study, we develop a new machine learning approach called PepBind-SVM to predict protein-binding peptides. To build this model, we extract different sequential and physicochemical features from peptides and use a Support Vector Machine (SVM) as the classification technique. We train this model on the dataset that we also introduce in this study. PepBind-SVM achieves 92.1% prediction accuracy, outperforming other classifiers at predicting protein-binding peptides. [ABSTRACT FROM AUTHOR]

This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1′s interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein–protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a "decoy" to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation. [ABSTRACT FROM AUTHOR]