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Since the discovery of magainins, cecropins and defensins 30 years ago, antimicrobial peptides (AMPs) have been hailed as a potential solution to the dearth of novel antibiotic development. AMPs have shown robust activity against a wide variety of pathogens, including drug-resistant bacteria. Unlike small-molecule antibiotics, however, AMPs have failed to translate this success to the clinic. Only the polymyxins, gramicidins, nisin and daptomycin are currently approved for medical use; the latter is the only example to have been developed in the last several decades. Nonetheless, researchers continue to isolate, modify and develop novel AMPs for therapeutic applications. Efforts have focused on increasing stability, reducing cytotoxicity, improving antimicrobial activity and incorporating AMPs in novel formulations, including nanoscale particles. As peptide synthesis and recombinant production methodologies improve, and more relevant bioassays become available, it becomes increasingly likely that AMPs will break the regulatory barrier and enter the marketplace as valuable antimicrobial weapons in the next 10 years.

Neurotropic viral infections continue to pose significant global health challenges, with pathogens such as herpes simplex virus (HSV), varicella‐zoster virus, human immunodeficiency virus, poliovirus, enteroviruses, parechovirus, West Nile virus and Japanese encephalitis virus driving the search for more effective therapeutic interventions. Current antiviral strategies, including small molecules and monoclonal antibodies, often face limitations such as drug resistance, narrow spectrum activity and adverse side effects, underscoring the need for alternative approaches. Antiviral peptides are emerging as potential therapeutic agents against these viral infections as entry and fusion inhibitors. However, their clinical development is limited by poor stability, low bioavailability and insufficient cellular penetration. To address these limitations, peptide stapling, a chemical modification that stabilises peptide α‐helices through covalent linkage, has emerged as a transformative technique to enhance the therapeutic potential of peptides, especially in antiviral drug development. Stapling techniques, including hydrocarbon staples, lactam bridges and metal‐coordination bonds, are explored for their ability to improve peptide stability, bioavailability and target binding affinity. This review examines the application of stapling in the development of antiviral peptides with a focus on stapled peptides targeting viral fusion and entry mechanisms, highlighting their potential against neurotropic viruses such as HSV and influenza. By integrating the structural rigidity conferred by stapling, these constructs promise to overcome delivery barriers and achieve superior antiviral efficacy. This paper underscores the pivotal role of peptide stapling by highlighting recent advancements in antiviral therapeutics and presents a roadmap for future research into multifunctional stapled peptides. Human neurotropic viruses like SARS‐CoV‐2, HSV, HOPV and RSV pose significant risks due to their ability to invade and persist in the nervous system. Stapled peptides represent a promising therapeutic approach with enhanced stability, target affinity and bioavailability, emerging as an effective strategy for neutralising human neurotropic viruses.

Purpose Quantitative targeted absolute proteomics (QTAP) quantifies proteins by measuring the signature peptides produced from target proteins by trypsin digestion. The selection of signature peptides is critical for reliable peptide quantification. The purpose of this study was to comprehensively assess the digestion efficiency and stability of tryptic peptides and to identify optimal signature peptides for human hepatic transporters and membrane marker proteins. Methods The plasma membrane fraction of the human liver was digested at different time points and the peptides were comprehensively quantified using quantitative proteomics. Transporters and membrane markers were quantified using the signature peptides by QTAP. Results Tryptic peptides were classified into clusters with low digestion efficiency, low stability, and high digestion efficiency and stability. Using the cluster information, we found that a proline residue next to the digestion site or the peptide position in or close to the transmembrane domains lowers digestion efficiency. A peptide containing cysteine at the N-terminus or arginine-glycine lowers peptide stability. Based on this information and the time course of peptide quantification, optimal signature peptides were identified for human hepatic transporters and membrane markers. The quantification of transporters with multiple signature peptides yielded consistent absolute values with less than 30% of coefficient variants in human liver microsomes and homogenates. Conclusions The signature peptides selected in the present study enabled the reliable quantification of human hepatic transporters. The QTAP protocol using these optimal signature peptides provides quantitative data on hepatic transporters usable for integrated pharmacokinetic studies.

Cardiovascular ailments are a major cause of mortality where over 1.3 billion people suffer from hypertension leading to heart-disease related deaths. Snake venoms possess a broad repertoire of natriuretic peptides with therapeutic potential for treating hypertension, congestive heart failure, and related cardiovascular disease. We now describe several taipan (Oxyuranus microlepidotus) natriuretic peptides TNPa-e which stimulated cGMP production through the natriuretic peptide receptor A (NPR-A) with higher potencies for the rat NPR-A (rNPR-A) over human NPR-A (hNPR-A). TNPc and TNPd were the most potent, demonstrating 100- and 560-fold selectivity for rNPR-A over hNPR-A. In vivo studies found that TNPc decreased diastolic and systolic blood pressure (BP) and increased heart rate (HR) in conscious normotensive rabbits, to a level that was similar to that of human atrial natriuretic peptide (hANP). TNPc also enhanced the bradycardia due to cardiac afferent stimulation (Bezold–Jarisch reflex). This indicated that TNPc possesses the ability to lower blood pressure and facilitate cardiac vagal afferent reflexes but unlike hANP does not produce tachycardia. The 3-dimensional structure of TNPc was well defined within the pharmacophoric disulfide ring, displaying two turn-like regions (RMSD = 1.15 Å). Further, its much greater biological stability together with its selectivity and potency will enhance its usefulness as a biological tool.

Advanced derivatives of the Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) have shown therapeutic efficacy upon topical administration in animal models of asthma and dermatitis. Here, we studied the plasma stability of the EPI-X4 lead compounds WSC02 and JM#21, using mass spectrometry to monitor the chemical integrity of the peptides and a functional fluorescence-based assay to determine peptide function in a CXCR4-antibody competition assay. Although mass spectrometry revealed very rapid disappearance of both peptides in human plasma within seconds, the functional assay revealed a significantly higher half-life of 9 min for EPI-X4 WSC02 and 6 min for EPI-X4 JM#21. Further analyses demonstrated that EPI-X4 WSC02 and EPI-X4 JM#21 interact with low molecular weight plasma components and serum albumin. Albumin binding is mediated by the formation of a disulfide bridge between Cys10 in the EPI-X4 peptides and Cys34 in albumin. These covalently linked albumin–peptide complexes have a higher stability in plasma as compared with the non-bound peptides and retain the ability to bind and antagonize CXCR4. Remarkably, chemically synthesized albumin-EPI-X4 conjugates coupled by non-breakable bonds have a drastically increased plasma stability of over 2 h. Thus, covalent coupling of EPI-X4 to albumin in vitro before administration or in vivo post administration may significantly increase the pharmacokinetic properties of this new class of CXCR4 antagonists.

Cyclodextrin-grafted polymers are attractive biomaterials that could bring together the host–guest complexing capability of pristine cyclodextrin and the pharmaceutical features of the polymeric backbone. The present paper is aimed at characterizing the potential application of ammonium–chitosan grafted with 2-methyl-β-cyclodextrin (N+-rCh-MCD) as the functional macromolecular complexing agent for the oral administration of the neuropeptide dalargin (DAL). Specific NMR characterization procedures, along with UV and fluorescence techniques, as well as biological in vitro assessments have been performed. The results indicate that N+-rCh-MCD forms water-soluble complexes with DAL, with a prevalent involvement of Tyr or Phe over Leu and Ala residues. The association constant of DAL with the polymeric derivative is one order of magnitude higher than that with the pristine cyclodextrin (Ka: 2600 M−1 and 120 M−1, respectively). Additionally, N+-rCh-MCD shields DAL from enzymatic degradation in gastrointestinal in vitro models with a three-fold time delay, suggesting a future pharmaceutical exploitation of the polymeric derivative. Therefore, the greater affinity of N+-rCh-MCD for DAL and its protective effect against enzymatic hydrolysis can be attributed to the synergistic cooperation between cyclodextrin and the polymer, which is realized only when the former is covalently linked to the latter.

The Azolla pinnata fern protein was enzymatically hydrolysed with Alcalase, Flavourzyme, and Papain at varying degrees of hydrolysis (10, 20, and 30%) to generate multi-biologically active protein hydrolysates. The extensively hydrolysed (30%) Alcalase-generated hydrolysate (AFPH-AE) was most active demonstrating antihypertensive (ACE inhibition), antidiabetic (DPP-IV, α-glucosidase, and α-amylase inhibition), and antioxidant (DPPH, ABTS, and FRAP) activities. AFPH-AE exhibited an uncompetitive inhibition mode against ACE and α-glucosidase, a mixed inhibition mode against α-amylase, and a noncompetitive inhibition mode against DPP-IV. This hydrolysate was highly stable under different food processing conditions including pH 5, 7, and 8, NaCl up to 150 mM, and a high temperature of 100 °C. The low molecular weight fraction (< 3 kDa) exhibited high biological activities, and a total of 15 low molecular weight bioactive peptides were identified. Molecular docking revealed that the peptide-enzyme interactions were mainly mediated via hydrogen bonds and hydrophobic interactions. Overall, these findings reveal the potential of AFPH-AE as a functional and/or nutraceutical ingredient with multifunctional antihypertensive, antidiabetic, and antioxidant effects.

Microbiologically influenced corrosion is a common problem in the industrial field due to the deterioration of metals in the presence of various microorganisms, in particular sulfate-reducing bacteria (SRB) and sulfur-oxidizing bacteria (SOB). A common method to reduce microbiologically influenced corrosion is the application of biocides. The limited number of suitable biocides and the resulting development of resistance, high dosage, and high application rate hinder an effective application. An environmentally friendly alternative could be the application of antimicrobial peptides (AMP), which have already been established in the field of medical devices for a while. Here, the successful treatment of different AMPs against 3 SRB and 1 SOB was demonstrated. The peptide L5K5W was favored due to its broad activity, high stability, and simple structure resulting in low synthesis costs. An alanine scan showed that substitution of leucine with tryptophan increased the activity of this peptide twofold compared to the original peptide against D. vulgaris, the main representative of SRB. Additional optimization of this modified peptide through changes in amino acid composition and lipidations significantly increased the effectiveness, finally resulting in a minimum inhibitory concentration (MIC) of 15.63 μg/mL against Desulfovibrio vulgaris. Even against the marine SRB Desulfovibrio indonesiensis with a required salt concentration of min. 2%, an activity of the peptides can be observed (MIC: 31.25 μg/mL). The peptides also remained stable and active for 7 days in the supernatant of the bacterial culture.Key points• Antimicrobial peptides provide an alternative to combat biocorrosive bacteria.• Optimization of the peptide sequence leads to a significant increase in activity.• The investigated peptides exhibit high stability, both in the medium and in the bacterial supernatant.

The application of nanotechnology in pharmaceutical delivery systems has provided innovative approaches to overcome the limitations of conventional antidiabetic therapies. Glucagon‐like peptide‐1 (GLP‐1) mimetics are potent therapeutic agents for type 2 diabetes mellitus; however, their short plasma half‐life, enzymatic degradation, and frequent dosing requirements restrict clinical outcomes. Nanoformulation strategies have shown substantial potential to enhance the pharmacokinetic and pharmacodynamic profiles of GLP‐1 mimetics through controlled release, protection from enzymatic degradation, and targeted delivery. This review provides a comprehensive overview of recent developments in nanoformulated GLP‐1 delivery systems, including lipid‐based carriers, polymeric nanoparticles, micelles, and hydrogel‐based delivery matrices. Emphasis is placed on formulation approaches that improve peptide stability, prolong circulation time, and facilitate site‐specific delivery to pancreatic or hepatic tissues. The discussion also includes key insights into physicochemical optimization, encapsulation efficiency, and stimuli‐responsive release mechanisms. Despite promising preclinical outcomes, translational progress remains limited, highlighting the necessity for in‐depth pharmacokinetic, safety, and scalability studies. Overall, nano‐enabled GLP‐1 delivery platforms represent a promising advancement toward more effective, patient‐friendly, and sustainable diabetes management solutions.

The development of new strategies to reduce the use of traditional antibiotics has been a topic of global interest due to the resistance generated by multiresistant microorganisms, including Escherichia coli, as etiological agents of various diseases. Antimicrobial peptides are presented as an alternative for the treatment of infectious diseases caused by this type of microorganism. The Ib−M1 peptide meets the requirements to be used as an antimicrobial compound. However, it is necessary to use strategies that generate protection and resist the conditions encountered in a biological system. Therefore, in this study, we synthesized alginate and chitosan nanoparticles (Alg−Chi NPs) using the ionic gelation technique, which allows for the crosslinking of polymeric chains arranged in nanostructures by intermolecular interactions that can be either covalent or non-covalent. Such interactions can be achieved through the use of crosslinking agents that facilitate this binding. This technique allows for immobilization of the Ib−M1 peptide to form an Ib−M1/Alg−Chi bioconjugate. SEM, DLS, and FT-IR were used to determine the structural features of the nanoparticles. We evaluated the biological activity against E. coli ATCC 25922 and Vero mammalian cells, as well as the stability at various temperatures, pH, and proteases, of Ib−M1 and Ib−M1/Alg-Chi. The results showed agglomerates of nanoparticles with average sizes of 150 nm; an MIC of 12.5 µM, which was maintained in the bioconjugate; and cytotoxicity values close to 40%. Stability was maintained against pH and temperature; in proteases, it was only evidenced against pepsin in Ib−M1/Alg-Chi. The results are promising with respect to the use of Ib−M1 and Ib−M1/Alg−Chi as possible antimicrobial agents.