Modification Of Peptides Research Articles

Controlling Nanonet Morphology via Residue-Specific Modulation of β-Hairpin Peptide for Enhanced Bacterial Trapping.

Precise control over peptide nanonet architecture is instrumental in advancing the development of antibacterial nanonets. Here, a novel design strategy is presented to control bacteria nanonet morphology through rational modification of the β-hairpin side strands, leveraging the unique chemical properties of amino acid side chains. By fine-tuning both the termini and aromaticity of the hydrophobic residue, the W-W13 peptide is engineered to form increased nanofibers interweaving on bacterial surfaces, forming a tightly interwoven nanonet that effectively traps and kills both E. coli and S. aureus. In contrast, asymmetric glutamic acid substitutions on the cationic residues of the E-E13 ASYM peptide redirect the nanofibers to self-interweave, forming extensive nanonets with minimal bacterial coverage and no antibacterial activity. Using these nanonets with distinct morphologies and function, it is demonstrated that the formation of tightly interwoven nanonets on bacterial surfaces significantly reduces the spread of motile E. coli and P. aeruginosa, outperforming both loosely trapping nanonets and conventional potent antibiotics. The findings pave the way for the development of novel peptide-based nanonets, offering a promising strategy to target bacterial motility and prevent spreading of bacteria.

Effect of solvent-induced packing transitions on N-capped diphenylalanine peptide crystal growth

Self-assembled supramolecular materials have gained extensive interest due to their ability to form structures with diverse physical, chemical, and biological properties. These characteristics arise from the precise arrangement of building blocks at the nanoscale. There is an unmet need to efficiently manipulate crystalline materials’ solid-state packing and monitor the effect on growth at a single crystal level. Herein, we used N-capped diphenylalanine peptide module to study the conditions affecting lattice configuration. In addition to the canonical monoclinic crystal, we found the peptide to alternatively assemble into an orthorhombic crystalline form. Wide-angle X-ray analysis indicated that the sharp transition between the distinct crystalline polymorphic forms depends on solvent composition, indicating the impact of the immediate molecular milieu on the monomeric conformation and the interactions with crystals. Both experimental and molecular dynamics simulations corroborate the results and demonstrate that solution composition directs the monomers to adopt specific conformations and affects their interactions with pre-formed crystal templates, resulting in either crystal growth, steady-state, or disassembly. These notions provide a profound understanding of crystal polymorphism and growth mechanisms at the molecular level, enabling the advanced design of bio-inspired materials.

Selective oxidative modification of tryptophan and cysteine residues using visible light responsive Rh doped SrTiO3 photocatalyst

In recent years, amino acids and peptides have attracted significant attention in food and medical fields due to their functionality. These functionalities largely depend on the chemical properties of their side chains, and efficient methods for selective side chain modification are desired. In this study, we investigated the selective modification of amino acids and peptides using rhodium-doped SrTiO3 (g-STO:Rh), a visible light-responsive photocatalyst. HPLC and LCMS analyses revealed that g-STO:Rh exhibited selective reactivity toward tryptophan and cysteine among the 20 protein-constituent amino acids. While cysteine was oxidatively dimerized to cystine, tryptophan underwent selective oxidation of its indole ring side chain, forming N-formylkynurenine. Furthermore, studies on dipeptides and tripeptides containing tryptophan have demonstrated that selective oxidation proceeds similarly to tryptophan residues within peptides.

Diet-induced mechanical stress promotes immune and metabolic alterations in the Drosophila melanogaster digestive tract.

Diet-induced mechanical stress promotes immune and metabolic alterations in the Drosophila melanogaster digestive tract.

Lesional Macrophage-Targeted Nanomedicine Regulating Cholesterol Homeostasis for the Treatment of Atherosclerosis.

The accumulation of atherosclerosis plaques within arterial walls leads to cardiovascular events. Lipid-laden macrophages, known as foam cells play a pivotal role in atherosclerotic plaque progression by disrupting cholesterol homeostasis and facilitating inflammation. This study presents a rational and multivalent nanoplatform (siTTENPs) for atherosclerosis treatment. siTTENPs can form electrostatic complexes with the nucleic acid siTRPM2, thereby reducing oxidized low-density lipoprotein (oxLDL) uptake by foam cells and alleviating inflammation. Concurrently, β-cyclodextrin (β-CD) modified siTTENPs facilitate cholesterol clearance, further re-establishing lipid homeostasis. The nanometer size and S2P peptide (CRTLLTVRKC) modification endow these particles with specific targeting capabilities toward lesional macrophages, thereby enhancing their anti-atherosclerotic efficacy. Consequently, the siTTENPs delivery system effectively inhibits pathological cholesterol internalization while simultaneously promoting cholesterol efflux mechanisms and reducing inflammation. This therapeutic intervention leads to significant regression of atherosclerotic plaque. This study introduces an innovative therapeutic strategy aimed at improving cholesterol homeostasis, with promising implications for the treatment of atherosclerosis.

Optimized strategies for designing antimicrobial peptides targeting multidrug-resistant Gram-negative bacteria.

Optimized strategies for designing antimicrobial peptides targeting multidrug-resistant Gram-negative bacteria.

Somatostatin receptor 2 targeting peptide modifications for peptide-drug conjugate treatment of small cell lung cancer.

Peptide-drug conjugate (PDC) represents a special therapeutic strategy to enhance drug delivery by targeting tumor cell receptors while minimizing off-target effects. Comparing the antibody-drug conjugate (ADC), the targeting peptide constitutes the pivotal component of PDC, especially with easy optimization of peptides to promote their in vivo stability, and with the agonist stimulated GPCR internalization to facilitate drug distribution into tumor cell plasma. Herein, we have optimized a highly stable peptide molecule LanTC targeting somatostatin receptor 2 (SSTR2), through amino acid substitution and disulfide bond modification from an FDA proved peptide drug Lanreotide. The LanTC based PDC was constructed through conjugation of the cytotoxic drug emtansine (DM1). The LanTC-DM1 PDC exhibited high stability and high agonist affinity to SSTR2. Subsequent in vitro and in vivo pharmacological data revealed that LanTC-DM1 PDC exhibited antitumor activity in small cell lung cancers (SCLC) which was known to have over-expressing SSTR2. The LanTC-DM1 PDC with specific targeting and antitumor activity provides a solid basis not only for advancing SSTR2-targeted PDCs as a promising therapy for SCLC, but also for other PDC developments targeting GPCRs in plasma membrane of tumor cells.

Arginine-N,N'-bisprenyltransferases: Switchable Catalysis in Consecutive Guanidine-N-prenylation.

Lipidation is a promising strategy to enhance the membrane affinity and the serum stability of peptide drugs. Cyanobactin prenyltransferases catalyze the prenylation of peptides with diverse chemoselectivity. Among these enzymes, AutF and AgcF catalyze the mono- and bisprenylations of Arg-Nω, respectively, although the structural basis for these distinct prenylation modes remained unknown. Through genome mining, we herein identified a new Arg-Nω-bisprenyltransferase, DciF, from Dolichospermum circinale AWQC310F. Crystallographic analysis and subsequent mutagenesis studies identified key active site residues that play pivotal roles in Arg-Nω-bisprenylation. Manipulations of the active site pocket successfully converted an Arg-Nω-bisprenyltransferase into an Arg-Nω-monoprenyltransferase, and vice versa, elucidating its role as a determinant factor for prenylation rounds. DciF efficiently catalyzed Arg-Nω-bisprenylation on various cyclic and linear peptides, demonstrating its remarkable potential as a biocatalytic tool for site-selective peptide modification. This study broadens the scope of biocatalytic peptide modifications and establishes a new framework for engineering cyanobactin prenyltransferases to control their prenylation rounds.

Chemoselective dual functionalization of proteins via 1,6-addition of thiols to trifunctional N-alkylpyridinium

Chemoselective dual functionalization of proteins has emerged as an invaluable tool to introduce two distinct payloads to proteins, thus greatly expanding their structural and functional repertoire for more advanced biomedical applications. Here, we introduce N-alkylpyridinium reagents as soft electrophiles for chemoselective dual modification of cysteine residues in peptides or proteins via a 1,6-addition reaction. The N-alkylpyridinium derivatives can be synthesized in two reaction steps revealing good water solubility, high labelling efficiency and chemoselectivity towards cysteine over lysine/N-terminal amine residues, even when used in large excess. This reaction can be combined with strain-promoted azide-alkyne click (SPAAC) and inverse-electron-demand Diels−Alder (iEDDA) reactions to achieve dual functionalization of proteins in a sequential simple one-pot reaction. As a proof-of-concept, the Rho-inhibiting enzyme Clostridium botulinum C3 is functionalized with a cancer cell-targeting peptide and a fluorescent dye for the inhibition of specific Rho-mediated intracellular pathways. The high stability, ease of synthesis, fast reaction kinetics, high water-solubility and chemoselectivity make N-alkylpyridinium reagents unique for dual modification of peptides and proteins to increase their functional diversities for medical applications.

Harnessing Organometallic Au(III) Complexes as Precision Scaffolds for Next-Generation Therapeutic and Imaging Agents.

Au(III) organometallic complexes, particularly cyclometalated Au(III) compounds, have emerged as powerful tools in catalysis and bioinorganic chemistry, offering unique reactivity distinct from their Au(I) counterparts. Among their most interesting transformations, C-S cross-coupling reactions have become a selective strategy for cysteine arylation, enabling site-specific modifications of peptides and proteins. This review provides a comprehensive overview of cyclometalated Au(III) complexes in C-S bond formation, detailing the mechanistic insights, ligand effects, and electronic factors that dictate their reactivity. The role of ancillary ligands in tuning stability and selectivity is critically assessed, alongside advancements in structural modifications that enhance catalytic efficiency. Beyond fundamental C-S cross-coupling, the broader applications of these Au(III) complexes are explored, including enzyme inhibition, metabolic disruption, and transmembrane protein modulation, with implications in anticancer therapy, antimicrobial strategies, and in vivo catalytic transformations. By bridging fundamental organometallic reactivity with innovative biomedical applications, this review highlights the potential of cyclometalated Au(III) complexes as next-generation catalysts for both synthetic and therapeutic innovations.

Modification of Peptide and Permeation Enhancer In Vitro Release Rates by Dispersion with a Gel-Forming Polymer

PurposeHerein, we evaluated the release properties of peptides when combined with a permeation enhancer (PE) as well as a gel-forming polymer.MethodsOctreotide was selected as a model hydrophilic peptide, while cyclosporine was chosen as a lipophilic peptide. The PEs studied were sodium decanoate (SD) and salcaprozate sodium (SNAC). To achieve synchronous release of the peptide and the PE, copovidone, a gel-forming polymer, was also included. Solid dispersions containing peptide, PE and polymer were prepared by dissolving all components in methanol followed by solvent removal. Dispersions were evaluated using powder X-ray diffraction. Surface normalized release rates of peptide, SNAC and copovidone alone and in combination were measured using Wood’s intrinsic dissolution rate apparatus.ResultsOctreotide dissolved rapidly while amorphous cyclosporine release rate was essentially undetectable. The PEs and neat polymer also dissolved rapidly. However, the intrinsic dissolution rates of octreotide and SNAC differed by a factor of two. Addition of copovidone to the formulation led to synchronous release of octreotide and SNAC, controlling their release. Furthermore, both SNAC and SD enhanced the dissolution rate of the polymer, leading to very rapid release of the components from the ternary dispersion. Cyclosporine released well from dispersions when present at a very low concentration, with a deterioration in release performance being observed at higher drug loadings.ConclusionsBased on the findings of this study, inclusion of a gel-forming polymer may help synchronize the release of a hydrophilic peptide and a PE, which in turn may improve co-localization at the epithelial membrane.Graphical

Protein-based nano delivery systems focusing on protein materials, fabrication strategies and applications in ischemic stroke intervention: A review.

Protein-based nano delivery systems focusing on protein materials, fabrication strategies and applications in ischemic stroke intervention: A review.

Neuropeptide Y receptors 1 and 2 as molecular targets in prostate and breast cancer therapy.

Neuropeptide Y receptors 1 and 2 as molecular targets in prostate and breast cancer therapy.

Natural Peptide Modulators of Ryanodine Receptors Produced by a High-Throughput Expression System

Natural Peptide Modulators of Ryanodine Receptors Produced by a High-Throughput Expression System

Analysis of isobaric quantitative proteomic data using TMT-Integrator and FragPipe computational platform

Isobaric mass tags, such as iTRAQ and TMT, are widely utilized for peptide and protein quantification in multiplex quantitative proteomics. We present TMT-Integrator, a bioinformatics tool for processing quantitation results from TMT and iTRAQ experiments, offering integrative reports at the gene, protein, peptide, and post-translational modification site levels. We demonstrate the versatility of TMT-Integrator using five publicly available TMT datasets: an E. coli dataset with 13 spike-in proteins, the clear cell renal cell carcinoma (ccRCC) whole proteome and phosphopeptide-enriched datasets from the Clinical Proteomic Tumor Analysis Consortium, and two human cell lysate datasets showcasing the latest advances with the Astral instrument and TMT 35-plex reagents. Integrated into the widely used FragPipe computational platform (https://fragpipe.nesvilab.org/), TMT-Integrator is a core component of TMT and iTRAQ data analysis workflows. We evaluate the FragPipe/TMT-Integrator analysis pipeline’s performance against MaxQuant and Proteome Discoverer with multiple benchmarks, facilitated by the bioinformatics tool OmicsEV. Our results show that FragPipe/TMT-Integrator quantifies more proteins in the E. coli and ccRCC whole proteome datasets, identifies more phosphorylated sites in the ccRCC phosphoproteome dataset, and delivers overall more robust quantification performance compared to other tools.

Controlled reversible methionine-selective sulfimidation of peptides

Site-selective chemical peptide manipulation is an effective strategy to understand and regulate structure and function. However, methionine-selective modification remains one of the most difficult challenges in peptide chemistry, with notable limited strategies. In this study, we report a general reversible modification strategy at methionine sites that uses the ruthenium-catalyzed sulfimidation of peptides. This method provides a convenient and effective strategy for late-stage peptide functionalization. The N═S bonds of the conjugates are reduced in the presence of glutathione, resulting the traceless releasing of corresponding peptides and amides. Practical applications are then demonstrated using precise reversible modifications of bioactive peptides, the stapling and linearization of peptides, peptide-drug conjugates, and split-and-pool synthesis. This on/off strategy through methionine-selective and reversible sulfimidation provides a unique tool for peptide chemistry and peptide-based drug discovery.

Annulative Editing of Peptide Side Chains: N-Pyridination of Lysine via Chichibabin Pyridine Synthesis in Hexafluoroisopropanol.

Modifying the lysine side chain through N-heteroaryl annulation offers a unique opportunity to tailor or edit the structure and properties of the parent peptides. Here, we report two new applications of the Chichibabin pyridine synthesis for lysine-specific peptide modification under mild conditions, employing two distinct classes of aldehyde reagents. Reactions with 2-arylacetaldehydes afforded symmetrical 3,5-diarylpyridinium products via an abnormal Chichibabin pathway, whereas reactions with 2-hydroxyacetaldehyde yielded unsymmetrical 3-hydroxy-4-hydroxylmethylpyridiniums (HHMP) products through an unusual, redox-neutral process. The use of a hexafluoroisopropanol (HFIP) solvent was crucial for the reactivity and selectivity in both reactions. Notably, these Lys-specific N-pyridination strategies demonstrated a rare tolerance toward highly nucleophilic cysteine residues.

Curcumin's multi-target mechanisms in the treatment of Alzheimer's disease and creative modification techniques.

Alzheimer's disease (AD) is a well-established neurodegenerative disorder characterized by memory impairment, cognitive dysfunction, and behavioral disturbances. With the global population aging, the prevalence of AD continues to rise, presenting significant challenges to both society and healthcare systems. Curcumin, a polyphenolic compound derived from turmeric rhizomes, has demonstrated considerable potential in AD treatment due to its anti-inflammatory, antioxidant, and neuroprotective properties. However, its clinical application remains constrained by chemical instability, poor water solubility, rapid metabolism, and accelerated elimination. To overcome these limitations, various curcumin derivatives have been synthesized, and combination therapy strategies have been explored. This review examines the potential mechanisms through which curcumin may exert therapeutic effects in AD, including the inhibition of neuroinflammation, regulation of tau protein hyperphosphorylation, modulation of amyloid-β peptides, and provision of antioxidant benefits. Additionally, the advantages of curcumin derivatives and combination therapy approaches are discussed, offering novel perspectives and promising strategies for AD treatment. It is anticipated that advancements in drug design and therapeutic approaches will contribute to the development of more effective treatment options for AD.

Design and inflammation-targeting efficiency assessment of an engineered liposome-based nanomedicine delivery system targeting E-selectin

To develop an E-selectin-targeting nanomedicine delivery system that competitively inhibits E-selectin-neutrophil ligand binding to block neutrophil adhesion to vessels and suppress their recruitment to the lesion sites. Doxorubicin hydrochloride (DOX)-loaded liposomes (IEL-Lip/DOX) conjugated with E-selectin-affinity peptide IELLQARC were developed using a post-insertion method. Two formulations [2-1P: Mol(PC): Mol(DPI)=100:1; 2-3P: 100:3] were prepared and their modification density and in vitro release characteristics were determined. Their targeting efficacy was assessed in a cell model of LPS-induced inflammation, a mouse model of acute lung injury (ALI), a rat femoral artery model of physical injury-induced inflammation, and a zebrafish model of local inflammation. The prepared IEL-Lip/DOX 2-1P and 2-3P had peptide modification densities of 4.76 and 7.57 pmoL/cm2, respectively. Compared with unmodified liposomes, IEL-Lip/DOX exhibited significantly reduced 48-h cumulative release rates at pH 5.5. In the inflammation cell model, IEL-Lip/DOX showed increased uptake by activated inflammatory endothelial cells, and 2-1P exhibited a higher trans-endothelial ability. In ALI mice, the fluorescence intensity of IEL-Lip/Cy5.5 increased significantly in lung tissues by 53.71% [Z-(2-1P)] and 93.41% [Z-(2-3P)], and 2-1P had an increased distribution by 24.19% in the inflammatory lung tissue compared to normal mouse lung tissue. In rat femoral artery models, 2-1P had greater injured/normal vessel fluorescence intensity contrast. In the zebrafish models, both 2-1P and 2-3P showed increased aggregation at the site of inflammation. This E-selectin-targeting nanomedicine delivery system efficiently targets activated inflammatory endothelial cells to increase drug concentration at the inflammatory site, which sheds light on new strategies for treating neutrophil-mediated inflammatory diseases and practicing the concept of "one drug for multiple diseases".

Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils.

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils, and fibrils, represents other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest; however, effective inhibitory peptides are often hydrophobic and hence difficult to handle. Therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.