A new series of pyridine-s-triazine-hydrazone derivatives was designed, synthesized via an efficient two-step route, and fully characterized by H-1-NMR, C-13-NMR, and elemental analyses. The compounds were evaluated for antiproliferative activity against A549 lung cancer cells and cytotoxicity toward WI-38 fibroblasts. All derivatives showed measurable activity, with 6f and 6j exhibiting superior potency (IC50 = 0.162 +/- 0.01 and 0.152 +/- 0.016 mu m) compared with sorafenib (0.195 +/- 0.02 mu m), along with improved safety and selectivity indices. Both compounds also demonstrated strong antitrypsin activity, moderate Factor Xa inhibition, and enhanced EGF inhibitory effects relative to sorafenib. Molecular docking revealed binding scores of -6.856 to -4.812 and MM-GBSA energies of -51.57 to -42.77 kcal/mol, exceeding those of sorafenib (docking score -4.805; Delta G-bind = -35.02 kcal/mol). Docking analyses also indicated potential dual inhibition via interactions at the EGFR active site and MEK1 allosteric site, indicating stronger predicted EGFR binding affinities than sorafenib supporting a multitarget mechanism. Overall, 6f and 6j emerge as promising lead candidates for further development as dual EGFR/MEK inhibitors with additional protease-modulating potential in NSCLC therapy.

ABSTRACT Classical structure–activity relationships (SAR) have limited predictive power for antimicrobial peptides (AMPs) because they assume fixed structures, single mechanisms, and independent physicochemical descriptors. In practice, AMP activity arises from dynamic, multistate ensembles that reorganize with environment, concentration, and membrane context. Here, we propose that the AMP function is best described using an ensemble‐based chemical framework grounded in free‐energy landscapes and interfacial thermodynamics. Peptide sequences encode distributions of chemically accessible states rather than unique bioactive conformations, while environmental variables selectively redistribute these populations across interfacial, inserted, and oligomeric regimes. Biological outcomes such as membrane disruption, intracellular access, and selectivity emerge as conditional consequences of state population shifts rather than intrinsic sequence‐encoded mechanisms. This perspective provides a chemically grounded alternative to static SAR and suggests that effective AMP design should focus on controlling ensemble redistribution under realistic interfacial environments.

Liquid-phase peptide synthesis (LPPS) continues to evolve toward more sustainable and efficient methodologies. In this study, we introduce Cyclover as a tag that enables efficient, tunable LPPS in 2Me-THF using propylphosphonic anhydride (T3P®) as a coupling reagent. The extraction protocol reduces the PMI ∼2.7-fold while maintaining high purity and isolated yield, offering a greener and versatile route to complex peptides

Four new crystal structures of OXYMA-B in its anionic form have been synthesized and structurally characterized via single-crystal X-ray diffraction. The new salts incorporate protonated amine-based cations including 1-phenylpiperazine (1PP), 1,4-dioxa-8-azaspiro[4.5]decane (DASD), ethylenediamine (ETDA), and pyrrolidine (Pyr), which function as efficient hydrogen bond (H-bond) donors. The electron-rich nature of the OXYMA-B anion provides multiple sites for H-bond acceptance, leading to diverse supramolecular synthons including R21(5), R21 (6), R24(8) and R34(12). The theoretical component of this study is based on density functional theory (DFT) calculations to dissect and characterize the individual H-bonded synthons using the quantum theory of atoms in molecules (QTAIM) framework. Additionally, interaction energies of discrete H-bonds have been quantified to rationalize their strength and directional preferences, showing that directional NH & sdot;& sdot;& sdot;O bonds contribute the most to the stability of the assemblies, with ancillary contacts playing a secondary but supportive role. The total interaction energies range from -34.0 to -50.0 kcal/mol, underscoring the critical role of hydrogen bonding in dictating the supramolecular architectures. This combined experimental-computational approach sheds light on the structural determinants driving supramolecular organization in OXYMA-B-based salts and highlights their potential for crystal engineering applications.

Solid-phase peptide synthesis (SPPS) remains the preferred method for peptide production, but traditional polystyrene (PS)-based resins often exhibit moderate swelling and aggregation during the synthesis of long or hydrophobic sequences. Polyethylene glycol (PEG)-modified resins improve solvation but typically suffer from reduced loading capacity. Here, we introduce Seplife Fmoc-RinkAmide-PS-PEG resin, a PEG-grafted PS support with optimized composition that combines good swelling with higher loading (0.37 mmol g(-1)) compared to a commercial PEG resin (0.27 mmol g(-1)). Its performance was evaluated in the synthesis of several peptides, including pentapeptides, ACP decapeptide, heptapeptide, afamelanotide, and the therapeutic peptide tirzepatide. In all cases, the resin enabled efficient couplings and afforded crude peptides of excellent purity (>95%-98% for small and medium-size peptides). These results demonstrate that Seplife Fmoc-RinkAmide-PS-PEG-resin provides a balanced alternative to existing PEG-based supports, combining high loading and reliable performance, and is particularly suitable for the synthesis of long or complex peptides.

Herein a straightforward and efficient method for synthesizing bromomaleimides with varied carbon chain lengths to modulate molecular properties has been reported. Compounds 1-4 incorporate a single bromomaleimide unit, while compound 5 features two, enabling dual functionalization. This synthetic approach consistently yields high-purity products in good to excellent yields, with compound 5 offering potential for dual payload conjugation due to its bifunctional structure. The key highlights are: 1. Bromomaleimides offers exceptional stability compared to maleimides counterparts 2. Highly selective for Cysteine modification.

One of the major health challenges in Chile's salmon industry is infestation by the ectoparasite Caligus rogercresseyi. Current treatments, primarily organophosphate compounds targeting acetylcholinesterase (AChE), are increasingly limited by resistance. This study investigates antimicrobial peptides (AMPs) from Atlantic salmon (Salmo salar) skin mucus as a potential alternative with lower risk of resistance and reduced environmental impact. Using a combination of in silico and in vitro approaches, a QSAR model screened 959 peptides, predicting 21 candidates with AChE inhibitory activity (IC50 < 100 mu M). These peptides were chemically synthesized and evaluated for antiparasitic activity against C. rogercresseyi nauplius, along with hemolytic and cytotoxic effects on salmon cells. Four peptides inhibited the nauplius stage with EC50 values ranging from 3 to 31 mu M at 48 and 72 h post-exposure. Among them, AS4532, AS4531, and AS4528 were confirmed as competitive AChE inhibitors, with Ki values of 64.8, 72.7, and 98.6 mu M, respectively. Notably, none of the peptides induced hemolysis or cytotoxicity. These findings provide the first evidence that fish mucus peptides can act as effective antiparasitic agents targeting AChE in C. rogercresseyi, offering a promising alternative to conventional chemical treatments.

The growing demand for therapeutic peptides has intensified concerns about the sustainability of current synthetic processes, which typically rely on excess reagents and, most critically, large volumes of solvents. In the pursuit of more sustainable practices, scientists now report a water-based synthetic protocol.

The synthesis of multiple antigenic peptides (MAPs) remains challenging and is conventionally achieved by using Lys-based branching cores. However, the presence of two asymmetric amino groups in Lys results in the formation of multiple isomeric impurities. To address this limitation, a novel symmetrical branching unit based on s-triazine, Fmoc2-TBM-OH (TBM for triazine-bis-multipod, 1), was synthesized and applied in MAP synthesis. The TBM-based strategy enabled efficient four-copy MAP synthesis and produced a less complex impurity profile, demonstrating improved robustness, chromatographic behavior, and synthetic practicality.

The transient, heterogeneous nano-bio interface defined by the protein corona in biological environments dictates the biodistribution, immune recognition, metabolism, and clearance of nanomaterials. Far from being a drawback, this corona can be harnessed for targeted nanodrug delivery when its composition is predictably tuned or deliberately modulated. We hypothesized that preloading apolipoprotein E (ApoE), previously identified as a constituent of the corona of β-sheet-breaker peptide-functionalized gold nanoparticles (AuNPs), would enhance transport across the blood-brain barrier (BBB) and increase brain uptake. To test this, we synthesized AuNPs (approximately 12 nm) functionalized (AuNP-f) with CLPFFD or THRPPMWSPVWPCLPFFD peptides, both containing the β-sheet-breaker motif LPFFD, which recognizes β-amyloid aggregates implicated in Alzheimer's disease. After incubation with human plasma, hard-corona proteins were profiled by 2D IEF/SDS-PAGE and LC-MS/MS. Proteins were ranked based on their roles in nanoparticle trafficking and BBB transcytosis, and ApoE was selected for deliberate enrichment due to its recurrent presence. ApoE-decorated AuNP-f were evaluated in an in vitro BBB model and in vivo biodistribution assays using Sprague-Dawley rats. Brain accumulation was assessed ex vivo. Preloading ApoE onto AuNP-f significantly enhanced nanoparticle transport across the BBB in vitro and increased brain accumulation in rats. These results demonstrate that rational corona enrichment with ApoE improves BBB transit and brain accumulation without altering nanoparticle surface chemistry. Corona engineering thus offers a pragmatic route to brain-targeted nanodrug delivery and may be extended to other protein-receptor axes for organ-specific targeting.

The elusive problem of an ideal protecting group for the arginine (Arg) side-chain still looms over solid-phase peptide synthesis (SPPS). While Pbf is widely accepted for maximizing incorporation of Arg, it still poses problems during the removal step, particularly for peptides containing multiple Arg. Here, we showcase the activation kinetics of Pbf, NO2, (Boc)2 and Suben protected Arg, elucidating the extent of side-reactions in each case. Pbf and NO2 show the least tendency for δ-lactamization, bis-Boc suffers from in-situ degradation to the mono-Boc and the Suben group facilitates the δ-lactamization step.

Process mass intensity (PMI) and complete E-factor (cEF) are widely accepted metrics for evaluating the sustainability of chemical processes, yet their routine application in peptide synthesis remains limited. This is primarily due to the perceived complexity and time required for mass accounting across repetitive coupling/deprotection cycles and solvent-intensive operations characteristic of both SPPS and LPPS. In this work, we present a simplified and practical approach for the rapid calculation of PMI and cEF specifically tailored to peptide synthesis workflows. The method is implemented through a user-friendly Excel-based tool that converts routinely recorded experimental parameters such as reaction scale, resin loading/tag, reagent, and solvent consumption into quantitative sustainability metrics using built-in formulas. The streamlined workflow allows PMI and cEF to be calculated within minutes without the need for specialized software or extensive additional data collection. By lowering the barrier to quantitative sustainability assessment, this method facilitates the routine inclusion of green metrics in method development, process optimization, and reporting. Importantly, the approach is equally relevant to academic and industrial laboratories, supporting informed decision-making and fostering the broader adoption of sustainability principles in peptide synthesis.

BACKGROUND:Chronic obstructive pulmonary disease (COPD) is characterized by sustained oxidative stress, inflammation, and epithelial damage. The transcription factor Nrf2 is a master regulator of antioxidant and cytoprotective defenses, and its dysregulation has been implicated in COPD pathogenesis. METHODS:We first investigated Nrf2 expression and its downstream antioxidant genes in lung tissue and neutrophils from healthy donors and COPD patients, and examined their association with disease severity (GOLD stage). We then compared the efficacy of two mechanistically distinct Nrf2 activators-omaveloxolone (an electrophilic compound) and LAS200813 (a peptide-based Keap1-Nrf2 protein-protein interaction inhibitor)-using bardoxolone methyl as a high-potency reference. Functional analyses were performed in human bronchial epithelial cells (HBECs) and peripheral blood neutrophils from both groups. RESULTS:Nrf2 and target gene expression were significantly reduced in COPD samples and correlated with disease severity, indicating pathway dysfunction. Pharmacological activation promoted Nrf2 nuclear translocation, restored redox balance, increased intracellular glutathione, and reduced ROS levels in epithelial and immune cells. Both activators induced HO-1 and NQO1 expression and attenuated cigarette smoke extract-induced release of IL-8, MMP-9, and IL-6, including in COPD-derived cells. In bronchial epithelial cells, Nrf2 activation was also associated with a reduction in CSE-induced apoptosis. Omaveloxolone showed slightly higher potency, while LAS200813 displayed comparable functional efficacy. CONCLUSION:These results confirm that the Nrf2 pathway is compromised in COPD and support selective Nrf2 activation-particularly via peptide-based approaches-as a promising therapeutic strategy to mitigate oxidative and inflammatory injury in the disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of cis-γ-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of γ-peptides in primary neuronal cultures to determine their effects on endogenous Aβ1-42 production, cytotoxicity, and β-secretase (BACE1)-associated activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with Aβ-lowering activity, establishing a qualitative structure-activity relationship. Peptide 33 (P33) emerged as a lead candidate, selectively reducing BACE1-associated activity without significantly inhibiting the associated activity of the homologous enzyme, BACE2. In vitro blood-brain barrier (BBB) assays revealed that P33 exhibits favorable transendothelial permeability. Intraperitoneal administration of P33 in APP/PS1 mice decreased Aβ levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity, and with no overt histopathological or selected neuroinflammatory changes. These results define cis-γ-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of Aβ production.

Polymyxins, particularly colistin, have re-emerged as last-line antibiotics against multidrug-resistant Gram-negative bacteria. Beyond their clinical revival, they represent a unique platform for medicinal chemistry, owing to their cyclic peptide scaffold, cationic diaminobutyric acid residues, and hydrophobic fatty acyl tail. Recent advances in solid-phase synthesis, structural biology, and molecular pharmacology have revealed critical structure-activity relationships (SAR) that govern antibacterial potency, toxicity, and resistance. This review highlights how chemical modification of Dab side chains, the N-terminal fatty acid, and the cyclic heptapeptide ring has led to next-generation analogues with improved efficacy and safety. We further discuss emerging synthetic strategies, mimetic design, and combination therapies that exploit polymyxin scaffolds to overcome resistance. These insights showcase polymyxins not merely as "old drugs" but as versatile chemical blueprints for innovative lipopeptide therapeutics targeting Gram-negative "superbugs".

A safety-catch protecting group allows for the use of the same reagent/chemical mechanism for the removal of different protecting groups in the same synthetic scheme. While the first of these is removed directly, the removal of the second requires previous manipulation to make the protecting group labile to the reagent. Herein, phenylthioethyl (Pte)- and phenylsulfonylethyl (Pse)-based protecting groups are described. While Pte is stable to piperidine, Pse, which is its oxidized form, is labile in the presence of DBU-methylpiperidine. This system allows the preparation of linear, branched, cyclic, and other complex peptides.

Until now, efforts to 'green' solid-phase peptide synthesis (SPPS) have largely focused on identifying a single solvent capable of replacing dimethylformamide, while relying exclusively on polystyrene-based resins. This approach has proven both challenging and limiting. Here, we propose that the most effective strategy for incorporating greener solvents into SPPS is to identify resin solvent combinations that can simultaneously support the two key reactions in peptide synthesis: coupling and Fmoc deprotection. When a relatively rigid resin is used, resin swelling is no longer a critical parameter in SPPS. This, in turn, enables the use of solvents that do not need to swell the resin, greatly expanding the range of greener solvent options that can be considered. This concept is exemplified by a novel polyacrylate-based rigid macroporous resin, which has enabled the SPPS synthesis of small- to medium-sized peptides using EtOAc, TEP, 2-MeTHF, acetone, and MeCN as single solvents.