Three complex ferrocene-BODIPY-fullerene-peptide conjugates were synthesized by successive CuAAC reactions between firstly ferrocene-BODIPY azides, then a lipoyl peptide azide, with a dual-clickable fullerene platform. These conjugates displayed broad absorption in the visible region due to their extended π-conjugation and the presence of an intramolecular charge transfer band from ferrocene to BODIPY, particularly in the case of BODIPY derivatives functionalized at the beta and alpha positions with ethynylFc and vinylFc groups, respectively. The terminal lipoyl peptide allowed grafting of the conjugates on gold surfaces, to form self-assembled monolayers that were characterized by PM-IRRAS and ultrafast electrochemical techniques. Estimation of the heterogeneous electron transfer rate constants for these monolayers revealed higher values for electron transfer from the BDP or C60 entities to the metal surface compared with conjugates without ferrocene units. This could be attributed to a reduced distance between the (Fc)2-BODIPY-C60 part and the metal surface, due to folding of the conjugates within the monolayer.

We screened for anti-ice-nucleation peptides using the phage display library method, with silver iodide as the target for artificial ice nucleation The phage interacted with the silver iodide in a dispersed state, rather than in an immobilized state. Based on DNA analysis, we identified five peptides with high expression levels. Five peptide sequences were synthesized by hand using the Fmoc solid-phase peptide synthesis and evaluated their anti-ice-nucleation activity. Three peptide sequences exhibited anti-ice-nucleation activity, and two of them were insoluble in water. Among the three peptides, SHIARSV exhibited the highest anti-ice-nucleation activity. To determine the importance of each amino acid in SHIARSV, we designed five peptides in which Ala was substituted and examined their anti-ice-nucleation activity. As a result, we identified AHIARSV, a peptide sequence with higher anti-ice-nucleation activity than the original SHIARSV sequence. This peptide exhibited high levels of both anti-nucleation activity and ice recrystallization inhibition activity. It is our conclusion that the design of antifreeze peptides with activities comparable with those of natural ones is highly feasible.

Here, we review solid-state NMR investigations of a variety of peptaibols in phospholipid bilayer environments. The peptides were prepared using different approaches such as microbial expression, solid-phase peptide synthesis or the chemical synthesis in solution and a modular fragment condensation approach. Importantly, the techniques allowed the preparation of peptaibols labelled with 19F as well as with 15N either uniformly or specifically. In a first approach, 15N-labelled peptides were reconstituted into uniaxially oriented bilayers to determine membrane alignment, structure and tilt angles. Whereas alamethicin (20 residues) tends to adopt transmembrane orientations, shorter peptaibols such as zervamicin IIB, ampullosporin A and trichogin show increasing preference for orientations parallel to the membrane surface. In a second set of experiments, magic angle spinning solid-state NMR spectroscopy experiments were performed. The CODEX experiments show the formation of oligomers in the membrane that increase in a concentration-dependent manner. Whereas for alamethicin transmembrane dimers (P/L 1/30) and pentamers (1/13) were observed, trichogin occurs as in-plane oriented tetramers (1/8). Interestingly, even the long alamethicin is oriented parallel to the membrane surface in a lipid composition mimicking bacterial membranes. These findings suggest that alternative mechanisms exist for the antimicrobial action of peptaibols.

The MDM2-p53 signaling axis governs the homeostatic balance between cell proliferation and apoptosis, and its aberrant activation drives tumor onset and progression. Disruption of this pathway therefore represents an effective strategy to suppress malignant growth. Here, the one-bead one-compound (OBOC) peptide library is designed to identify self-assembling peptide leads that specifically target MDM2. Differently from conventional static inhibitory peptides, the identified peptides exhibit unique target-triggered self-assembly behavior upon specific binding to MDM2 protein. The peptides first bind MDM2 with high nanomolar affinity and subsequently assemble into dense nanofibrous structures in situ, which sterically and efficiently disrupt the MDM2-p53 interaction. In vitro cellular assays demonstrate that these self-assembled peptide nanofibers remarkably suppress tumor cell proliferation and migration. Collectively, this work discovers a novel class of MDM2-targeting peptides with programmable self-assembly property, providing an innovative structural design strategy and promising precursor candidates for future MDM2-p53 pathway-targeted antitumor research.

Human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-secreted with insulin from pancreatic β-cells, undergoes self-assembly into cytotoxic amyloid fibrils in the pathogenesis of type 2 diabetes (T2D). The resulting islet amyloid deposits are implicated in progressive β-cell dysfunction and loss, making hIAPP aggregation an attractive therapeutic target. Nonhuman islet amyloid polypeptide (IAPP) orthologs have recently emerged as a valuable source of mechanistic insight, with several variants-including raccoon and chicken IAPPs-demonstrating the capacity to inhibit hIAPP fibril formation. Here, the biophysical characterization of red panda (Ailurus fulgens) IAPP (rpIAPP) and its effects on hIAPP aggregation are reported. Using thioflavin T fluorescence assays, circular dichroism spectroscopy, and atomic force microscopy, red panda IAPP is found to inhibit hIAPP fibrillation at substoichiometric concentrations, with significant inhibitory activity observed at molar ratios as low as 1:0.5 (hIAPP:rpIAPP). These results position red panda IAPP as one of the more potent nonhuman IAPP inhibitors characterized to date and support its further evaluation as a scaffold for the rational design of peptide-based therapeutics targeting T2D-associated amyloidogenesis.

The automation of the azapeptide submonomer synthesis procedure is reported. All steps for on-resin aza-amino acid synthesis, including semicarbazone incorporation, alkylation, deprotection, and semicarbazide acylation were adapted for use on a commercially available peptide synthesizer. Key requirements for success included the use of a stable isocyanate precursor for the semicarbazone installation, the use of stable reagents in DMF, and elimination of cooling steps. The synthesis of > 30 azapeptides was accomplished using our optimized automated submonomer azapeptide synthesis procedure.

A sustainable synthetic strategy for Fmoc-protected pseudoproline dipeptides was developed to address the environmental and operational limitations of traditional solvent-intensive methods. By utilizing ethanol as solvent during cyclisation, activated ester formation, and coupling steps, this approach eliminates the need for hazardous conventional solvents while simplifying the overall process. The protocol consistently delivers pseudoproline dipeptides in high yields and with excellent purity, demonstrating that environmentally friendly modifications can maintain strong synthetic performance. In addition to its operational simplicity and scalability, the method significantly reduces solvent-related hazards, minimizes waste generation, and improves key green chemistry. This practical and versatile methodology provides a cleaner, more sustainable platform for the synthesis of pseudoproline-containing intermediates relevant to peptide and pharmaceutical manufacturing.

The global rise of multidrug-resistant (MDR) pathogens has created an urgent need for alternative antimicrobial agents. In this study, we evaluated the antibacterial activity of LTX-315, a synthetic cationic 9-mer peptide originally developed as an oncolytic agent, against six ATCC reference strains and six clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae, MDR Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. LTX-315 exhibited broad-spectrum antibacterial activity, with MICs of 8-32 μM against reference strains and as low as 4 μM against several MDR clinical isolates, whereas chloramphenicol and kanamycin were ineffective. Double-disk diffusion assays indicated synergistic interactions with aminoglycosides, chloramphenicol, and vancomycin, and checkerboard assays confirmed synergy-to-additivity interactions with gentamicin and vancomycin against S. aureus (FICI 0.38-0.75), yielding fourfold to 16-fold reductions in antibiotic dose. These findings demonstrate that LTX-315 retains potent activity against clinically relevant MDR pathogens and may serve as both a standalone antimicrobial peptide and a potential antibiotic adjuvant.

Glypican-3 (GPC-3) is a cell-surface glycoprotein, highly expressed in hepatocellular carcinoma (HCC) but largely absent in normal adult liver tissues, making it a clinically compelling biomarker and therapeutic target. Although monoclonal antibodies and antibody-drug conjugates have proven to be GPC-3-targeted therapies, their large molecular size, slow pharmacokinetics, and potential immunogenicity limit their diagnostic applications. Peptide ligands offer an attractive alternative owing to their low molecular weight, rapid tumor penetration, favorable clearance profiles, synthetic accessibility, and ease of chemical modification. This topical review highlights the development of linear and cyclic GPC-3-binding peptides over the past two decades, developed primarily via phage display, rational optimization, and structure-guided approaches, enabling PET, SPECT, and fluorescence imaging of HCC in preclinical models. Recent refinements, including albumin-binding modifications and cyclization strategies, have improved tumor-to-liver contrast and in vivo stability. This review summarizes the biological significance of GPC-3, compares peptides and peptide probes as targeting modalities, and critically analyzes recent advances in linear and cyclic peptide-based GPC-3 imaging probes. We also emphasized the importance, current challenges, and future opportunities in AI/ML-based design of peptide ligands for HCC theranostics.

Candida parapsilosis (C. parapsilosis) has caused more infections in recent years, and resistance to conventional antifungal agents is also rising. This study evaluated the antifungal potential of a newly designed MAF-1A-derived peptide against C. parapsilosis. Four derivatives were chemically synthesized and structurally characterized. Our hybrid method included the use of computational tools for hydrophobic optimization, amphipathic α-helix stabilization, and peptide-membrane interaction prediction together with experimental validations. We synthesized four designed derivatives (8KGF7, 9GIF6, 10KLF6, and 10GIF6) by Fmoc-based solid-phase chemistry. Its antifungal activity against C. parapsilosis was assessed using the broth microdilution assay. Trypsin stability was evaluated by incubating 10KLF6 with trypsin followed by measurement of residual antifungal activity. Hemolytic safety was assessed using human red blood cells via hemolytic activity assays. The results demonstrated that 10KLF6 exhibited up to 15-fold higher antifungal activity against C. parapsilosis compared to MAF-1A. Additionally, 10KLF6 retained more than 20% of its antifungal activity after 100 min of trypsin digestion and showed low hemolytic toxicity. Collectively, 10KLF6 possesses potent antifungal activity as well as favorable stability and safety profiles against C. parapsilosis, which supports its further exploration as a promising candidate for the development of potent and stable antifungal peptide agents.

Peptide nucleic acids (PNAs) are a promising platform targeting disease-associated microRNAs due to their high binding affinity, excellent sequence specificity and resistance to enzymatic degradation. However, their therapeutic application is often limited by inefficient cellular uptake. In this study, we present the design, synthesis and physicochemical characterisation of cell-penetrating peptide (CPP)-PNA conjugates that target the oncogenic microRNA miRNA-221-5p, as well as their preliminary biological evaluation. Anti-miRNA-221-5p PNAs functionalised for conjugation with CPPs via Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) or disulfide-mediated coupling were synthesised using solid-phase peptide synthesis. Circular dichroism and UV-melting analyses confirmed the formation of a stable, sequence-specific PNA-RNA heteroduplex with miRNA-221-5p. This demonstrated strong hybridisation and high thermodynamic stability compared to scrambled control sequences. Cell proliferation assays indicated modest but reproducible antiproliferative effects for the CPP-PNA conjugates co-incubated with chloroquine, with no evidence of acute cytotoxicity. These findings emphasise the potential of CPP-PNA systems for the intracellular delivery of antisense agents and highlight the importance of the linker nature in determining their biological performance.

Plant-derived peptides represent a rich source of structurally diverse and biologically potent scaffolds, characterized by high stability and a wide range of mechanisms of action. This review examines the structure-activity relationships (SAR) of these peptides, focusing on how key structural features-including disulfide connectivity, loop architecture, charge distribution, and backbone cyclization-govern their biological activity, selectivity, and toxicity. Representative peptide families such as cyclotides, defensins, thionins, and snakins are discussed to highlight conserved structural motifs alongside variable regions that contribute to functional diversity. We further explore rational design and engineering strategies, including loop grafting, cyclization, charge modulation, and backbone stabilization, supported by selected case studies demonstrating improved pharmacological profiles, membrane interactions, and target specificity. Building on these insights, we propose a design-oriented framework that integrates SAR-guided peptide engineering with experimental toxicology and pharmacological evaluation to facilitate the development of plant-derived peptides as therapeutic leads and molecular tools. This peptide-centric perspective aims to complement existing studies on plant bioactive peptides and to advance the rational design of next-generation peptide-based therapeutics.

Broad-spectrum insecticides persist in the environment, affecting non-target organisms and selecting for resistant pest populations. In contrast, RNA interference (RNAi) achieves species-targeted pest control triggered by the delivery of exogenous double-stranded RNA (dsRNA), which is biodegradable and broken down into harmless components by nucleases. Sprayable applications require suitable formulation strategies for dsRNA protection during delivery. Here, we describe the preparation of dsRNA-lipopeptide complexes (LPCs) composed of non-toxic short-chain lipopeptide surfactants by microfluidic mixing, yielding positively charged dispersions of LPCs < 200 nm in diameter, which encapsulate and protect dsRNA from enzymatic degradation. Some lipopeptides were found to undergo thermo-reversible gelation, self-assembling to fibrillar nanostructures, but remained effective for dsRNA delivery to induce mortality in Colorado potato beetle larvae feeding on sprayed plants. Our results show that lipopeptide surfactants are suitable for the formulation of dsRNA to enable effective delivery to pest insects.

Hydrogen bonds contribute substantially to the stabilisation of specific three-dimensional structures of peptides. The C5 hydrogen bond is an intraresidue interaction, which appears to contribute to the stabilisation of fully extended residue conformations, with backbone torsion angles (φ, ψ) lying close to ±180°. The present study revisits the occurrence of C5 conformations in proteins, using a high-resolution, non-homologous dataset of 6924 x-ray diffraction structures (sequence identity < 30%, resolution < 1.6 Å). Gly emerges as the residue with the highest propensity to adopt C5 conformations, followed by Ser. Residues with branched sidechains Leu, Val and Ile are strongly disfavoured. Specific examples in protein structures that have contiguous residues in C5 conformations are highlighted.