International Journal of Peptide Research and Therapeutics最新文献

Background

The emergence of multidrug-resistant pathogens through excessive and indiscriminate use of antibiotics, together with the lack of highly efficient treatment options for bacterial infections, has raised the development of novel antimicrobial agents to top priority. In this context, cryptic host defense peptides (cHDPs) are being explored as a novel class of antimicrobial agents. In this study, short peptides were designed from the long nonantibacterial protein ToAP2 and analysed for their positive net charge, hydrophobicity, hydrophobic moment, hydrophobic and hydrophilic planes.

Methods

From the designed fragments, five 15 amino acid fragments were synthesised by solid-phase peptide synthesis (SPPS) and analysed for antimicrobial activity against ESKAPE pathogens. All the peptides were subject to cytotoxicity, mode of action, structure and function studies to find the best template for further optimisation.

Results

Among them, two peptides, FKL15 and SKL15, showed better efficiency in killing P. aeruginosa under physiological salt and plasma conditions with no cytotoxicity issues. Further, the peptides destroyed the bacterial membranes and adopted a random coil structure in the presence of the bacteria.

Conclusions

The data indicates that FKL15 and SKL15 are promising antimicrobial peptides against antibiotic-resistant bacteria with great potential to develop as drugs with high economic value.

Purpose

This study investigates the regulatory role of NL13, a compound derived from adenosyl homocysteinase of cyanobacteria, on ER stress-induced apoptosis in endothelial cells by modulating the Keap1-Nrf2 signaling pathway.

Methods

Human endothelial cells (EA.hy926) were exposed to thapsigargin (TPG) to induce ER stress and then pretreated with varying concentrations of NL13. The study employed qPCR to assess changes in gene expression related to ER stress markers (GRP78, CHOP, ATF6, and PERK) and Nrf2. Additionally, reactive oxygen species (ROS) levels and the expression of apoptotic proteins (Bcl2 and Bax) were evaluated. In-silico molecular docking was used to explore potential interactions between NL13 and Keap1-Nrf2.

Results

NL13 significantly reduced oxidative and ER stress in endothelial cells. It downregulated ER stress markers (GRP78, CHOP, ATF6, PERK) while upregulating Nrf2 expression. NL13 also decreased ROS formation and modulated the expression of apoptotic proteins, increasing Bcl2 and decreasing Bax. Molecular docking revealed interactions of NL13 with critical amino acids in Keap1-Nrf2, suggesting a functional binding that enhances Nrf2 signaling.

Conclusion

NL13 exerts cytoprotective effects against ER stress in endothelial cells by modulating the Keap1-Nrf2 signaling pathway and reducing apoptosis. These findings highlight the potential of NL13 as a therapeutic agent for conditions involving ER stress and oxidative damage.

Background

With the rising demand for peptide-based drugs, enhancing their stability against proteolytic degradation has become a critical challenge. Strategies to improve peptide stability include cyclization, substitution of L-amino acids with D-amino acids, incorporation of β-amino acids, and various formulation techniques. An innovative approach involves modifying the peptide backbone by reversing the amide bond direction and inverting the stereochemistry of amino acids in the same segment. This approach results in the formation of retro-inverso peptides, which offer increased stability, permeability, and cellular uptake.

Purpose

The aim of this review is to provide a comprehensive analysis of retro-inverso peptides, focusing on their concept, synthesis, and applications as potential therapeutic agents, drug delivery systems, and in aesthetic applications.

Methods

The review explores the theoretical underpinnings of retro-inverso peptide design and its application to both linear and cyclic peptides. The synthesis strategies of retro-inverso peptides are discussed in detail, along with their formulation and practical utility in various biomedical fields.

Results

Retro-inverso peptides show promise in enhancing peptide stability and improving biological properties such as permeability and cellular uptake. Their unique structure offers advantages in drug development and potential as therapeutic agents or drug carriers.

Conclusion

Retro-inverso peptides represent a valuable strategy for overcoming the limitations of conventional peptides, especially regarding stability and bioavailability. This review highlights their potential in therapeutic development and other applications, reinforcing the importance of continued research and innovation in peptide chemistry.

Nosocomial infections caused by antibiotic-resistant bacteria result in significant economic costs and human health issues, including acute lung injury. The purpose of this study was to investigate the scorpion venom in countering lung injury induced by bacterial sepsis. Androctonus crassicauda (Acra) scorpion venom was fractionated using HPLC and tested against bacteria. The anti-bacterial fraction obtained at 36th min (AcraX) was used to generate chitosan-coated particles. Following induction of sepsis in rats, they were administered venom on the sixth hour and sacrificed at 24 h. Lung tissues were used for histopathological analyses and after homogenization, for cytokine (TNF-α, IL-1β, IL-6, and IL-10) measurements by ELISA. Immunohistochemical examinations were performed in terms of extracellular matrix and fibrosis using anti-MMP-2 and MMP-9 antibodies. Among the bacterial strains used in our research for the antibacterial effect of AcraX (S.aureus, K.pneumoniae, A.baumannii, and P.aeruginosa), positive results were obtained only against Klebsiella pneumoniae. The regenerative effect of the venom against lesions developed in tissue and HeLa cell line was also observed. 100% vitality was achieved in the HeLa cell line exposed to the venom. This was also observed histologically via changes in the alveolar septa in lung tissue sections and a decrease in areas of inflammation and the hyaline membrane structure in the sepsis group. In conclusion, Acra venom acts as an efficient anti-inflammatory agent against K. pneumoniae induced pneumoniae.

Knowledge of plant-based medicines in the Uttarakhand region is extensive, and these remedies are utilized for preventive and curative purposes. Traditional medical knowledge and herbal remedies form the backbone of primary health care system. The native plants in Uttarakhand are essential to the local tribes because they can produce food and medicine. Examples include Buransh (Rhododendron) flowers, Sal (Shorea robusta), Chora (Angelica glauca), Timuru (Zanthoxylum armatum), Jatamansi (Nardostachys), Kutki (Picrorhiza kurroa), Brahma Kamal (Saussurea obvallata). The diverse range of plants in this area may be explored for antimicrobial peptides (AMPs) or proteins that can serve as alternative treatments to combat resistant Gram-positive and Gram-negative bacteria effectively. Given the ever-increasing drug resistance among clinical pathogens, the value of novel AMPs is particularly relevant. In plants, the distinguishing feature of antimicrobial peptides (AMPs) lies in the plentiful occurrence of cysteine residues, which contribute to the formation of numerous disulfide bonds. Several plant AMP families exist as defensins, hairpin-like peptides, thionins, knottin-type peptides (cyclic and linear), snakins, α-hairpins, and lipid transfer proteins. Some plants AMPs possess high levels of amino acids other than cysteine. Plant AMPs have the unique capability to cluster into distinct families and share conserved structural folds. Over time, computational approaches have gained prominence in understanding the crucial facets of antimicrobial peptides (AMPs). These approaches offer the advantage of reducing the time and expense associated with traditional wet lab experiments. Several databases and tools have been created to aid researchers in providing up-to-date details on AMPs. However, despite the growing possibility of AMP resources in biological repositories, locating plant-derived AMPs remains challenging.

The prevalence of cancer is so high globally that it is imperative to identify effective treatments. The use of bee products in the field of cancer therapeutics has gained significant attention as a promising alternative. Female worker bees (Apis mellifera) produce bee venom, which contains a complex array of biologically active compounds, including enzymes and peptides. Bee venom exhibits a range of biological activities with potential human health benefits, which vary across bee species and geographic locations. The objective of this study was to investigate the cytotoxicity of Turkish bee venom for the first time on some of the selected cancer cell lines. Bee venom was collected and resuspended in water and ethanol. The study analyzed both forms of Turkish bee venom for major peptides and proteins using HPLC-VWD and SDS-PAGE. The major components identified were apamin, melittin, phospholipase A2, and hyaluronidase. Cytotoxic activities were evaluated on eight distinct cell lines (seven cancerous cells and one control) using MTT assays. The Turkish bee venom demonstrated cytotoxicity with 48-hour IC50 values of 14.8 ± 0.6, 5.7 ± 0.2, 8.1 ± 0.1, 7.1 ± 0.1, 8.5 ± 0.2, 7.2 ± 0.1, 7.9 ± 0.1, and 8.0 ± 0.1 µg/mL for Phoenix-AMPHO (CRL-3213), PC-3, Huh-7, Caco-2, HT-29, SW-48, CARM-L12 TG3, and A-673, respectively. The 72-hour IC50 values were 8.2 ± 0.2, 4.5 ± 0.3, 7.1 ± 0.1, 6.4 ± 0.1, 6.0 ± 0.3, 7.2 ± 0.1, 2.1 ± 0.1, and 6.0 ± 0.2 µg/mL, respectively. In conclusion, the study demonstrated that both forms of Turkish bee venom exhibited significant cytotoxic effects on the analyzed cancer cells. The cell lines CARM-L12 TG3, PC-3, and A-673 exhibited the most pronounced responses to the bee venom.

The scorpion-derived peptide margatoxin (MgTx) can make it possible to create novel and targeted medications for treatment of cancer. In this study, for the first time, we report an investigation of the human serum albumin (HSA) protein interaction with MgTx in aqueous solution. For this, biophysical methods including spectral, surface plasmon resonance (SPR), zeta potential and also in silico molecular docking technique at physiological conditions were used for examining kinetic binding and thermodynamic data. This interaction was done for a series of MgTx concentrations at three temperatures. The comparison of the K_D kinetic value at 308 ° K and 298 ° K in SPR and UV spectroscopy shows that the complex between the MgTx and HSA has high strength at lower temperatures. The resulted positive data for ΔH and ΔS show that the major interaction force involved in the formation of the MgTx/HSA complex is hydrophobic forces. Also, the decreasing of zeta-potential values by adding of MgTx concentrations confims that the MgTx molecules could bind to HSA more by hydrophobic forces. In addition, according to the docking results, there are a very small number of strong interactions such as hydrogen bonds and salt bridges compared to the hydrophobic forces in the HSA and MgTx interaction.

Graphical Abstract

Angiotensin-converting enzyme-2 (ACE2) is a important cell surface receptor of SARS-CoV-2 S protein. The initial stage of SARS-COV-2 cell infection involves the binding of the S protein to ACE2. Hence, this work presents an innovative strategy to designing ACE2-based peptide inhibitors by considering the surface property and morphology of the S protein RBD. The aim is to develop a short peptide inhibitor that can effectively inhibit S protein-ACE2 interaction Through computational analysis and molecular simulation, the surface properties and morphology of S protein receptor-binding structural domain (RBD) were investigated, while the key residues of ACE2 ligand-binding structural domain (LBD) were identified based on their contributions and non-covalent interactions. Then, peptide inhibitors, consisting of ACE2 key residues, were developed by fitting to the surface characteristics and topographical features of the S protein RBD. Molecular simulation showed that two novel short peptides, IEPFF (I5) and WIEPFF (W6) had high affinity for S protein RBD but a low affinity for the cell membrane. Cellular adsorption studies demonstrated that both I5 and W6 effectively blocked ACE2-S protein binding without significant cytotoxicity. Flow cytometry analysis revealed that both I5 and W6 effectively inhibited S protein binding to the ACE2, resulting in a significant reduction (75 and 79%, respectively) in fluorescence intensity after 30 min of incubation at a concentration of 200 μM. Both I5 and W6 were excellent potential anti SARS-COV-2 drugs. This work provides an innovative perspective for the development of functional peptides for the prevention and management of SARS-COV-2.

The rapid emergence of multidrug-resistant (MDR) bacteria has motivated researchers to develop new antibiotic agents including antimicrobial adjuvants that resensitise against multidrug-resistance. In this study, four peptides, two 12-mer and two 8-mer derived from the primary structure of human glucose-dependent insulinotropic polypeptide (GIP), were synthesized by solid-phase peptide synthesis (SPPS). These peptides were designated as AO1, AO2, AO3, and AO4, respectively. Their antimicrobial activity was tested against bacteria possessing an AcrAB-TolC efflux pump system, namely Escherichia coli TG1 and Erwinia amylovora 1189. Although the peptides were shown to have no antimicrobial activity, through a synergistic action they each reduced the MIC values of the selected AcrAB-TolC antibiotic substrates by 4 to 8-fold in E. coli TG1 and 4 to 16-fold in E. amylovora 1189. The activity of synthetic peptides as AcrAB-TolC inhibitors in E. coli TG1 and E. amylovora 1189 was tested by intercellular ethidium bromide (EtBr) accumulation assay at different concentrations ranging from 12.5 to 100 µg mL^− 1. When compared to a reference efflux pump inhibitor, the four peptides each demonstrated good inhibitory action, with the optimum being 100 µg mL^− 1. Our results show these to be promising lead peptides for further development as potential antibacterial adjuvants against MDR bacteria.

Neglected tropical diseases (NTDs) are a group of at least 20 infectious diseases that primarily affect tropical regions. Despite impacting 1.6 billion people worldwide, these diseases have not received adequate global priority and attention. Currently, NTDs caused by protozoa have limited therapeutic options, and the emergence of drug-resistant strains further exacerbates the situation. In recent years, several antimicrobial peptides (AMPs) have emerged as potential therapeutic candidates against NTDs. This review analyzes the contemporary trends of AMPs, explores their antiparasitic properties, and mechanisms of action against three parasitic protozoan NTDs: Chagas disease, human African trypanosomiasis, and leishmaniasis and one parasitic helminth NTD: lymphatic filariasis. Furthermore, notable drawbacks associated with AMPs are highlighted, and future research directions are proposed. Overall, this review points out the potential of AMPs as therapeutic agents for these three protozoan neglected tropical diseases and one parasitic helminth NTDs as well as emphasizes the imperative need for continued research in this field.