Aug 2026· Journal of Peptide Science· Vol 32· 0 citations· 33 references
Medicine
TL;DR
The synthesis and in vitro neuronal growth support activity of a novel series of heptapeptides promote neuronal survival, morphology recovery, increase cell proliferation, and preserve neuronal network integrity under OGD/R and hypoxia/R insult in an in vitro model of ischemic stroke.
Abstract
ABSTRACT The synthesis and in vitro neuronal growth support activity of a novel series of heptapeptides (1–19) are reported here. Structural studies of the peptide 3 (LSAVTFG.DMA) revealed an unexpected dimethylammonium (DMA) salt adduct formation localized at the C‐terminal glycine residue. DOSY NMR analysis revealed the presence of two distinct species exhibiting different diffusion coefficients, allowing the differentiation between the peptide and the DMA adduct. Peptide 3 promoted neural differentiation at 100 μM concentration. To identify residues crucial for biological activity, we conducted L‐ and D‐alanine scans with salt and nonsalt form of peptide 3, which resulted in the synthesis of 16 peptide analogs. Findings from the alanine scan revealed that the lead peptides L1A.DMA (13) and S2A.DMA (15) exhibited significant neural progenitor cells or neural stem cells (NPCs/NSCs) differentiation activity. These peptides promote neuronal survival, morphology recovery, increase cell proliferation, and preserve neuronal network integrity under OGD/R and hypoxia/R insult in an in vitro model of ischemic stroke. These results represent the first synthetic approach to new neuromodulatory peptides and deliver important structure–activity relationship (SAR) insights to guide the development of bioactive peptides.
Bisecting GlcNAc, a central branch in N-glycans synthesized by the N-acetylglucosaminyltransferase III (MGAT3; also known as GnT-III), is highly expressed in neurons. Although pathological roles of MGAT3 and bisecting GlcNAc have been demonstrated in Alzheimer's disease, their physiological functions in neurons remain unclear. To identify their physiological functions, here we examine the morphology of neurons in knockout (Mgat3-/-) mouse brains and investigate the expression and localization of bisecting GlcNAc-bearing glycoproteins involved in neuronal activity and morphogenesis. We found impaired neurite extension and spine maturation in cultured cortical neurons of Mgat3-/- mice, along with reduced stimulus-induced in vivo neuronal activity. Moreover, key glycoproteins for these processes (specifically α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA]-type glutamate receptors) showed reduced accumulation in postsynaptic density membrane fractions and a weakened interaction with transmembrane AMPA receptor regulatory protein 8 (TARP8) in Mgat3-/- mouse brain. These results suggest that bisecting GlcNAc plays important roles in synaptic maturation, highlighting a new mechanism for neuronal activity regulated by specific N-glycans.
Yuta Hashimoto, Wanxue Bao, Shun Yamaguchi et al.· Biochemical Journal· 0 citations
Selenium nanoparticles (Se-NPs) were manufactured effectively by a green chemical reduction approach utilizing sodium selenite and ascorbic acid, resulting in stable, rod-like nanoparticles with an average particle size of 23.5 nm and a high surface area of 25.05 m²/g. These Se-NPs were utilized as effective nanocatalysts in the chemical synthesis of new coumarin-based glycinate and heterocyclic amide derivatives via esterification and nucleophilic substitution reactions, markedly improving reaction rates and yields relative to traditional approaches. The resultant organic compounds (C1, C2, C6, C8, C9) were subsequently immobilized onto Se-NPs, resulting in stable core–shell nanostructures, as verified by UV–Vis spectroscopy and TEM imaging. The structural elucidation of the produced compounds was conducted utilizing FTIR, ¹H NMR, and ¹³C NMR spectroscopy. The acetylcholinesterase (AChE) inhibitory assay revealed that C6 (IC₅₀ = 8.0 ± 0.24 µM) and C9–Se-NPs (IC₅₀ = 1.19 ± 0.04 µM) exhibited enhanced inhibitory activity compared to the standard drug (IC₅₀ = 11.41 ± 0.35 µM), whereas C8 showed a higher IC₅₀ value (13.0 ± 0.54 µM), indicating lower activity. Upon nanoparticle conjugation, a significant reduction in IC₅₀ was observed for C6 (from 8.0 ± 0.24 to 4.64 ± 0.14 µM) and C8 (from 13.0 ± 0.54 to 5.272 ± 0.161 µM). Although C9–Se-NPs (1.19 ± 0.04 µM) exhibited a higher IC₅₀ than the parent compound C9 (0.50 ± 0.01 µM), it remained markedly more potent than all other tested compounds in both free and nano-conjugated forms. Overall, these findings suggest that Se-NPs act as effective nanocatalysts for organic transformations and as efficient carriers that enhance the biological activity of the conjugated compounds, supporting their potential application as multifunctional platforms for neuroprotective therapy in Alzheimer’s disease.
B. Farag, Wesam S. Shehab, Hanan F. Aly et al.· Scientific Reports· 0 citations
A series of amide-linked cholic acid derivatives (3a–f) was synthesized through an efficient one-pot acyl chloride coupling strategy, yielding structurally diverse hybrids under mild conditions. The antioxidant potential of these derivatives was evaluated using the DPPH radical scavenging assay, with compounds 3b–d exhibiting the most pronounced activity, in an average of 50%. Antibacterial efficacy was investigated against both Staphylococcus aureus and Escherichia coli, revealing preferential activity toward Gram-positive strains, particularly for aromatic amide-bearing analogs. To elucidate the underlying molecular interactions, in silico investigations, including molecular docking, molecular dynamics simulations, and MM-PBSA binding free energy calculations, were conducted against the ATP-binding domain of bacterial DNA gyrase (GyrB). These computational studies revealed stable binding modes and favorable energetics that correlate with observed bioactivity. Density functional theory and ADMET predictions further supported the drug-like profiles and chemical reactivity of the most active compounds. These results demonstrate that the cholic acid scaffold can be effectively tailored to yield multifunctional agents with antioxidant and selective antibacterial properties, providing a promising framework for the development of novel antimicrobial candidates.
Talha Mashhood, Akbar Ali, Eman Fatima et al.· RSC Advances· 0 citations
Lanthanides (Lns) have recently been recognized as essential cofactors for certain bacterial enzymes, such as methanol dehydrogenase (MDH), yet their poor bioavailability under physiological conditions has long suggested the existence of Ln-binding metallophores termed lanthanophores. In this context methylolanthanin (MLL), a chelator which is potentially involved in Ln-uptake of methylotrophic bacteria, was recently isolated and characterized. Herein we synthesized two novel MLL derivatives, ortho- and meta-MLL, for comparative studies in order to gain a deeper insight into the unusual 4-hydroxy benzoate moiety of native para-MLL. For this we implemented UV-vis titrations, time-resolved laser-induced fluorescence spectroscopy (TRLFS) and ion mobility spectrometry-mass spectrometry (IMS-MS) complemented by density functional theory (DFT) calculations to investigate metal-binding behavior in both solution and gas phases to trivalent Lns. As our binding studies revealed that both artificial chelators tend to precipitate Lns similar to the native para-MLL under biologically relevant conditions (pH: 6.0), rather than solubilizing them, the solubility products of their Eu3+ complexes were determined. Due to the structural resemblance of the MLL derivatives to the siderophore rhodopetrobactin B (RPB B), we also investigated iron binding. In this regard ortho-MLL stood out in our analysis and showed a distinctly different binding behavior from the other two derivatives.
M. Mertens, Sarah L Hügel, Oliver Hagen et al.· Dalton Transactions· 0 citations
Short self-assembling peptides are versatile building blocks for enzyme-responsive nanostructured biomaterials. Here, we investigate how
N
-terminal acetylation affects the stability, fibrillogenesis, and protease-mediated fragment formation of two modular peptides, ug51 and ug52, composed of a fibrillogenic QAGIVV segment, an MMP-7-cleavable PLGL linker, and a
C
-terminal domain derived from motifs related to osteogenic growth peptides (OGPs). The stability of the peptides was assessed in water and cell culture medium, while secondary structure and nanoassembly were analyzed by circular dichroism, thioflavin T fluorescence, and transmission electron microscopy (TEM). Biological effects were evaluated in hFOB 1.19 osteoblasts. The non-acetylated peptide ug51 underwent spontaneous cleavage in the Val-Pro region, generating defined fragments, including PLGLYGFGG and, after prolonged incubation, the OGP-related LYGFGG sequence. In contrast, the
N
-terminally acetylated analog ug52 displayed markedly higher stability and formed ThT-positive, TEM-visible fibrillar assemblies. These assemblies remained susceptible to MMP-7-mediated processing, as shown by MALDI-TOF MS detection of the LYGFGG fragment after enzymatic incubation. Biological assays in hFOB 1.19 osteoblasts indicated overall cytocompatibility within the tested concentration range and peptide- and fragment-dependent effects on metabolic/proliferation-associated activity and migration-related responses. These findings suggest that
N
-terminal acetylation can shift the behavior of this modular peptide system from spontaneous degradation toward a more stable, fibril-forming, protease-processable state. Thus, this study provides proof-of-concept evidence that
N
-terminal acetylation can modulate the balance between peptide stability, supramolecular assembly, and enzymatic processability in a short modular peptide system.
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N-terminal acetylation increases the apparent stability of the modular peptide ug52.
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Non-acetylated ug51 undergoes spontaneous Val-Pro cleavage.
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Acetylated ug52 forms ThT/TEM-positive fibrils that remain MMP-7-processable.
Agnieszka Kubiś, J. Sawicka, M. Włodarczyk et al.· Applied Microbiology and Bio...· 0 citations
Non-enzymatic glycosylation of proteins leads to the formation of advanced glycation end products (AGEs), implicated in oxidative stress and the progression of several chronic diseases. Among the reactive carbonyl compounds, methylglyoxal (MGO) is highly potent in inducing glycoxidative damage by modifying proteins. Herein, we investigated the protective effect of plumbagin, a naphthoquinone derived from Plumbago zeylanica, to counteract MGO-induced glycation of catalase, employing integrated biophysical and computational approaches. AGE-specific fluorescence at 335 and 370 nm, ThT dye fluorescence, and microscopic visualizations confirmed that plumbagin markedly reduces AGEs formation and aggregation. Fluorescence quenching experiments revealed a stable catalase-plumbagin complex formation having binding affinity (Ka): 0.205 × 106 M-1 and a stoichiometry of one binding site (n ≈ 1.1), suggesting a single, specific binding pocket. Isothermal titration calorimetry (ITC) confirmed an exothermic, enthalpy-driven interaction. Molecular dynamics simulations (MDS) analysis displayed a more compact and ordered conformation of complex, as evidenced by reduced Rg, SASA, and RMSF values. H-bonds stabilized the complex without altering the catalytic residues (His74, Asn147, Tyr357). PCA and FEL showed complex remained confined to a single deep energy minimum, indicating enhanced thermodynamic stability. These findings highlight plumbagin as a potent multifunctional compound capable of mitigating MGO-induced glycation.
Faiza Iram, Ayesha Aiman, Deepanshi Vijh et al.· Journal of Cellular Biochemi...· 0 citations