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14 pages, 2719 KiB  
Article
Combinatorial Effects of CPP-Modified Antimicrobial Peptides: Synergistic and Additive Interactions Against Pathogenic Bacteria
by Oxana V. Galzitskaya, Sergey V. Kravchenko, Sergei Y. Grishin, Alena P. Zakhareva, Leila G. Mustaeva, Elena Y. Gorbunova, Alexey K. Surin and Viacheslav N. Azev
Int. J. Mol. Sci. 2025, 26(13), 5968; https://doi.org/10.3390/ijms26135968 - 21 Jun 2025
Viewed by 440
Abstract
The development of novel antimicrobial peptides (AMPs) with broad-spectrum activity represents a promising strategy to overcome multidrug resistance in pathogenic bacteria. In this study, we investigated the antimicrobial activity of three designed peptides—R44KS*, V31KS*, and R23FS*—engineered to [...] Read more.
The development of novel antimicrobial peptides (AMPs) with broad-spectrum activity represents a promising strategy to overcome multidrug resistance in pathogenic bacteria. In this study, we investigated the antimicrobial activity of three designed peptides—R44KS*, V31KS*, and R23FS*—engineered to incorporate an amyloidogenic fragment from the S1 protein of Staphylococcus aureus and one or two cell-penetrating peptide (CPP) fragments to enhance cellular uptake. The antimicrobial efficacy of these peptides and their combinations was assessed against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Bacillus cereus. The results demonstrated that all three peptides exhibited significant antibacterial activity in a concentration-dependent manner, with R44KS* being the most potent. Peptide combinations, particularly V31KS*/R23FS* and R44KS*/V31KS*, showed enhanced inhibitory effects and reduced minimum inhibitory concentrations (MICs), suggesting synergistic or additive interactions. Fractional inhibitory concentration index (FICI) analysis confirmed that most combinations exhibited synergy or additive effects. These findings highlight the potential of CPP-modified peptides as antimicrobial agents and underscore the importance of optimizing peptide combinations for therapeutic applications. Full article
(This article belongs to the Section Molecular Microbiology)
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18 pages, 2973 KiB  
Article
A TAT Peptide-Functionalized Liposome Delivery Phage System (TAT-Lip@PHM) for an Enhanced Eradication of Intracellular MRSA
by Kaixin Liu, Xin Lu, Xudong Guo, Yi Yang, Wanying Liu, Hongbin Song and Rongtao Zhao
Pharmaceutics 2025, 17(6), 743; https://doi.org/10.3390/pharmaceutics17060743 - 5 Jun 2025
Viewed by 548
Abstract
Background: Intracellular bacteria frequently result in chronic and recurrent infections. MRSA is one of the most prevalent facultative intracellular bacteria in clinical infections. The drug resistance of MRSA and the difficulty of most antibiotics in entering cells result in a suboptimal clinical efficacy [...] Read more.
Background: Intracellular bacteria frequently result in chronic and recurrent infections. MRSA is one of the most prevalent facultative intracellular bacteria in clinical infections. The drug resistance of MRSA and the difficulty of most antibiotics in entering cells result in a suboptimal clinical efficacy of antibiotics in the treatment of intracellular MRSA. Bacteriophages represent a promising alternative therapy in the context of the current antimicrobial resistance crisis. Nevertheless, the low efficiency of phage entry into cells and their rapid inactivation remain challenges in the treatment of intracellular MRSA using phages. The utilization of functionalized carriers for the delivery of phages into cells and their protection represents a feasible strategy. Methods: In this study, a new MRSA bacteriophage (vB_SauS_PHM) was isolated from hospital sewage, exhibiting the characteristics of short incubation period, large lytic amount, and good environmental tolerance. Subsequently, vB_SauS_PHM was encapsulated by TAT peptide-functionalized liposomes through microfluidic technology and size-exclusion chromatography (SEC), forming a phage delivery system, designated TAT-Lip@PHM. Results: The encapsulation rate of the phage by TAT-Lip@PHM was 20.3%, and the cell entry efficiency was ≥90% after 8 h. The 24 h eradication rate of 300 μg/mL TAT-Lip@PHM against intracellular MRSA was 94.05% (superior to the 21.24% and 44.90% of vB_SauS_PHM and Lip@PHM, respectively), while the mammalian cell activity was >85% after 24 h incubation. Conclusions: The TAT-Lip@PHM effectively delivered the phage into the cell and showed an excellent killing effect on intracellular MRSA with low cytotoxicity. This work provides a technical reference for the application of phages in the treatment of intracellular bacterial infection. Full article
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15 pages, 1908 KiB  
Article
Surface Functionalized Polyhydroxyalkanoate Nanoparticles via SpyTag–SpyCatcher System for Targeted Breast Cancer Treatment
by Jin Young Heo, Min Kyung Sung, Seonhye Jang, Hansol Kim, Youngdo Jeong, Dong-Jin Jang, Sang-Jae Lee, Seong-Bo Kim and Sung Tae Kim
Pharmaceutics 2025, 17(6), 721; https://doi.org/10.3390/pharmaceutics17060721 - 29 May 2025
Viewed by 635
Abstract
Background/Objectives: Biodegradable polymers have emerged as promising platforms for drug delivery. Produced by microbiomes, polyhydroxyalkanoates (PHAs) offer excellent biocompatibility, biodegradability, and environmental sustainability. In this study, we report the surface functionalization of PHA-based nanoparticles (NPs) using the SpyTag–SpyCatcher system to enhance cellular uptake. [...] Read more.
Background/Objectives: Biodegradable polymers have emerged as promising platforms for drug delivery. Produced by microbiomes, polyhydroxyalkanoates (PHAs) offer excellent biocompatibility, biodegradability, and environmental sustainability. In this study, we report the surface functionalization of PHA-based nanoparticles (NPs) using the SpyTag–SpyCatcher system to enhance cellular uptake. Methods: Initial conjugation with mEGFP-SpyTag enabled visualization, followed by decoration with HER2-specific Affibody-SpyCatcher and/or TAT-SpyCatcher peptides. The prepared NPs retained a diameter of <200 nm and a negatively charged surface. Results: Affibody-functionalized NPs significantly enhanced internalization and cytotoxicity in HER2-overexpressing SK-BR-3 cells, whereas TAT-functionalized NPs promoted uptake across various cell types, independently of HER2 expression. Dual-functionalized NPs exhibited synergistic or attenuated effects based on the HER2 expression levels, highlighting the critical role of ligand composition in targeted delivery. Conclusions: The results of this study demonstrate that the SpyTag–SpyCatcher-mediated surface engineering of PHA NPs offers a modular and robust strategy for active targeting in nanomedicine. Full article
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13 pages, 3591 KiB  
Article
Synergistic Engineering of the Twin-Arginine Translocation (Tat) Pathway and Membrane Capacity Enhances Extracellular Production of Amylosucrase in Bacillus licheniformis
by Caizhe Wang, Dandan Niu, Yongqing Zhou, Hui Liu, Nokuthula Peace Mchunu, Meng Zhang, Suren Singh and Zhengxiang Wang
Microorganisms 2025, 13(6), 1179; https://doi.org/10.3390/microorganisms13061179 - 22 May 2025
Viewed by 384
Abstract
Amylosucrase (AS) is a highly versatile enzyme with significant potential for industrial applications, including functional food production and glycosylation of bioactive compounds. However, its large-scale production is hampered by low secretion efficiency in microbial hosts. This study focuses on engineering the twin-arginine translocation [...] Read more.
Amylosucrase (AS) is a highly versatile enzyme with significant potential for industrial applications, including functional food production and glycosylation of bioactive compounds. However, its large-scale production is hampered by low secretion efficiency in microbial hosts. This study focuses on engineering the twin-arginine translocation (TAT) pathway and optimizing membrane resource allocation in Bacillus licheniformis to enhance the extracellular production of Neisseria polysaccharea amylosucrase (NpAS). The investigation integrates three targeted strategies: optimizing the hydrophobic region adjacent to the TAT signal peptide, modifying TAT translocases via site-directed mutagenesis, and improving inter-pathway membrane resource redistribution by deleting non-essential Sec pathway components. Among the engineered strains, BLΔDF93S-2.0AS1 achieved an extracellular enzyme activity of 706.10 U/L, equating to a 2.01-fold improvement over the parental strain. These results emphasize the potential of combining multifaceted engineering strategies to optimize heterologous protein secretion systems. Full article
(This article belongs to the Special Issue Advances in Microbial Cell Factories, 3rd Edition)
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12 pages, 1743 KiB  
Article
Cell-Penetrating Peptide Based on Myosin Phosphatase Target Subunit Sequence Mediates Myosin Phosphatase Activity
by Andrea Kiss, Mohamad Mahfood, Zsófia Bodogán, Zoltán Kónya, Bálint Bécsi and Ferenc Erdődi
Biomolecules 2025, 15(5), 705; https://doi.org/10.3390/biom15050705 - 12 May 2025
Cited by 1 | Viewed by 492
Abstract
Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The [...] Read more.
Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The association of MYPT1 with PP1c increases the phosphatase activity toward myosin; therefore, disrupting/dissociating this interaction may result in inhibition of the dephosphorylation of myosin. In this study, we probed how MYPT132–58 peptide including major PP1c interactive regions coupled with biotin and cell-penetrating TAT sequence (biotin-TAT-MYPT1) may influence MP activity. Biotin-TAT-MYPT1 inhibited the activity of MP holoenzyme and affinity chromatography as well as surface plasmon resonance (SPR) binding studies established its stable association with PP1c. Biotin-TAT-MYPT1 competed for binding to PP1c with immobilized GST-MYPT1 in SPR assays and it partially relieved PP1c inhibition by thiophosphorylated (on Thr696 and Thr853) MYPT1. Moreover, biotin-TAT-MYPT1 dissociated PP1c from immunoprecipitated PP1c-MYPT1 complex implying its holoenzyme disrupting ability. Biotin-TAT-MYPT1 penetrated into A7r5 smooth muscle cells localized in the cytoplasm and nucleus and exerted inhibition on MP with a parallel increase in MLC20 phosphorylation. Our results imply that the biotin-TAT-MYPT1 peptide may serve as a specific MP regulatory cell-penetrating peptide as well as possibly being applicable to further development for pharmacological interventions. Full article
(This article belongs to the Section Enzymology)
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22 pages, 5179 KiB  
Article
Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment
by Samar Zabit, Orly Melloul, Michal Lichtenstein, Erin L. Seifert and Haya Lorberboum-Galski
Int. J. Mol. Sci. 2025, 26(9), 4379; https://doi.org/10.3390/ijms26094379 - 5 May 2025
Viewed by 2864
Abstract
The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (Pi) into the mitochondrial matrix for ATP production and other [...] Read more.
The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (Pi) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca2+ uptake and buffering of matrix Ca2+. PiC also imports copper (Cu), crucial to COX subunit holoenzyme assembly. Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life. We have developed a novel therapeutic approach using TAT-mPiC fusion protein for cellular delivery since the TAT peptide enables delivery of proteins across biological membranes. We designed, produced, and purified the TAT-mPiC fusion protein. The fusion protein is delivered into the mitochondria and localizes within the mIM, its natural cellular location, as a processed protein. Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion. Most importantly, TAT-mPiC restored Pi and Cu delivery into the mitochondrial matrix. TAT-mPiC fusion protein also restored the mitochondrial activity of cells harboring various mitochondrial defects. This study presents the first successful delivery of a mitochondrial transmembrane carrier using the TAT-fusion system, offering a potential early treatment strategy for newborns with mPiC deficiency. Full article
(This article belongs to the Section Molecular Biology)
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19 pages, 3289 KiB  
Article
Genome Mining of the Biocontrol Agent Trichoderma afroharzianum Unearths a Key Gene in the Biosynthesis of Anti-Fungal Volatile Sesquiterpenoids
by Fang Zhang, Rui Ma, Yuyang Huang, Yang Cui, Qiong Zhou and Jingang Gu
Catalysts 2025, 15(4), 341; https://doi.org/10.3390/catal15040341 - 1 Apr 2025
Cited by 1 | Viewed by 680
Abstract
The volatile organic compounds (VOCs) in Trichoderma afroharzianum ACCC 33109 have the biological activities of both hydrolytic enzymes and antimicrobial peptides to mitigate attack by phytopathogens and spread over long distances in soil. However, the biosynthesis pathway of anti-fungal VOCs has not been [...] Read more.
The volatile organic compounds (VOCs) in Trichoderma afroharzianum ACCC 33109 have the biological activities of both hydrolytic enzymes and antimicrobial peptides to mitigate attack by phytopathogens and spread over long distances in soil. However, the biosynthesis pathway of anti-fungal VOCs has not been elucidated yet. In this study, we identified 15 genes (TaTS115) coding for putative terpene synthase with low identities (<79.54%) to functionally characterized homologs through genome mining. Upon Fusarium induction, the relative expression levels of nine TaTS genes were up-regulated by up to 2793-fold (TaTS9). To verify the contribution of TaTS9 to the synthesis of anti-fungal VOCs, the TaTS9 knockout mutant strain was constructed and characterized by its antagonistic activities, transcript profiles, and VOC metabolomes. Heterologous expression of TaTS9 in Escherichia coli produced the target gene product, which converted the precursor farnesyl pyrophosphate (FPP) into β-cubenene (>90%) and γ-amorphene. Thus, TaTS9 was confirmed as the first β-cubenene synthase of Trichoderma, which catalyzes the biosynthesis of various sesquiterpenes with anti-fungal activities. This study provides insight into the key terpene synthase gene in the biosynthesis of anti-fungal sesquiterpenoids for potential applications in the agriculture and food industries. Full article
(This article belongs to the Section Biocatalysis)
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22 pages, 6177 KiB  
Article
The Virus Entry Pathway Determines Sensitivity to the Antiviral Peptide TAT-I24
by Eva Kicker, Antonio Kouros, Kurt Zatloukal and Hanna Harant
Viruses 2025, 17(4), 458; https://doi.org/10.3390/v17040458 - 23 Mar 2025
Viewed by 2905
Abstract
The peptide TAT-I24, a fusion of the TAT peptide (amino acids 48–60) and the 9-mer peptide I24, has been previously shown to neutralize several double-stranded (ds) DNA viruses in vitro. We have now extended the testing to potentially sensitive RNA viruses and analyzed [...] Read more.
The peptide TAT-I24, a fusion of the TAT peptide (amino acids 48–60) and the 9-mer peptide I24, has been previously shown to neutralize several double-stranded (ds) DNA viruses in vitro. We have now extended the testing to potentially sensitive RNA viruses and analyzed the antiviral effect of the peptide against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). In Vero E6 cells, TAT-I24 neutralized the human 2019-nCoV isolate (Wuhan variant) in a dose-dependent manner, while it was unable to neutralize two SARS-CoV-2 variants of concern, Delta and Omicron. Moreover, TAT-I24 could not significantly neutralize any of the SARS-CoV-2 variants in the human lung carcinoma cell line Calu-3, which provides an alternative entry route for SARS-CoV-2 by direct membrane fusion. Therefore, a possible dependence on virus uptake by endocytosis was investigated by exposing Vero E6 cells to chloroquine (CQ), an inhibitor of endosomal acidification. The Wuhan variant was highly sensitive to inhibition by CQ, an effect which was further enhanced by TAT-I24, while the Delta variant was less sensitive to inhibition by higher concentrations of CQ compared to the Wuhan variant. The microscopic analysis of COS-7 cells using a rhodamine-labeled TAT-I24 (Rho-TAT-I24) showed the endosomal localization of fluorescent TAT-I24 and co-localization with transfected GFP-Rab14 but not GFP-Rab5. As these proteins are found in distinct endosomal pathways, our results indicate that the virus entry pathway determines sensitivity to the peptide. Full article
(This article belongs to the Special Issue Antiviral Peptide)
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15 pages, 3240 KiB  
Article
Therapeutic Effects of TN13 Peptide on Acute Respiratory Distress Syndrome and Sepsis Models In Vivo
by Jae-Eun Byun, Jae-Won Lee, Eun Ji Choi, Juhyun Lee, Seok Han Yun, Chan Ho Park, Hanna Kim, Mi Sun Kim, Suk Ran Yoon, Tae-Don Kim, Ji-Yoon Noh, Sang-Hyun Min, Hyun-A. Seong, Kyung-Seop Ahn, Inpyo Choi and Haiyoung Jung
J. Clin. Med. 2025, 14(6), 1804; https://doi.org/10.3390/jcm14061804 - 7 Mar 2025
Viewed by 931
Abstract
Background/Objectives: Regulation of acute inflammatory responses is crucial for host mortality and morbidity induced by pathogens. The pathogenesis of acute respiratory distress syndrome (ARDS) and sepsis are associated with systemic inflammation. p38 MAPK is a crucial regulator of inflammatory responses and is a [...] Read more.
Background/Objectives: Regulation of acute inflammatory responses is crucial for host mortality and morbidity induced by pathogens. The pathogenesis of acute respiratory distress syndrome (ARDS) and sepsis are associated with systemic inflammation. p38 MAPK is a crucial regulator of inflammatory responses and is a potential target for acute inflammatory diseases, including ARDS and sepsis. We investigated the therapeutic effects of the TAT-TN13 peptide (TN13) on severe inflammatory diseases, including ARDS and sepsis, in vivo. Methods: To establish the ARDS model, C57BL/6 mice were intranasally (i.n.) administered lipopolysaccharide (LPS; 5 mg/kg, 40 µL) to induce lung inflammation. As a positive control, dexamethasone (DEX; 0.2 mg/kg) was administered intraperitoneally (i.n.) 1 h post-LPS exposure. In the experimental groups, TN13 was administered intranasally (i.n.) at doses of 2.5 mg or 5 mg/kg at the same time point. In the LPS-induced sepsis model, mice received an intraperitoneal injection of LPS (20 mg/kg) to induce systemic inflammation. TN13 (25 mg/kg, i.p.) was administered 1 h after LPS treatment. Control mice received phosphate-buffered saline (PBS). Lung histopathology, inflammatory cell infiltration, cytokine levels, and survival rates were assessed to evaluate TN13 efficacy. Results: TN13 significantly reduced inflammatory cell recruitment and cytokine production in the lungs, thereby mitigating LPS-induced ARDS. In the sepsis model, TN13 treatment improved survival rates by suppressing inflammatory responses. Mechanistically, TN13 exerted its effects by inhibiting the p38 MAPK/NF-κB signaling pathway. Conclusions: These results collectively suggested that TN13 could be an effective treatment option for severe inflammatory diseases. Full article
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19 pages, 3367 KiB  
Article
Differentiation of Isomeric TAT1-CARNOSINE Peptides by Energy-Resolved Mass Spectrometry and Principal Component Analysis
by Alicia Maroto, Olivier Briand, Alessia Distefano, Filiz Arioz, Olivier Monasson, Elisa Peroni, Giuseppe Grasso, Christine Enjalbal and Antony Memboeuf
Molecules 2025, 30(4), 853; https://doi.org/10.3390/molecules30040853 - 12 Feb 2025
Viewed by 998
Abstract
L-carnosine (Car) is an endogenous dipeptide with significant potential in drug discovery for neurodegenerative diseases, while TAT1, a small arginine-rich peptide derived from the HIV-1 trans-activator protein (TAT), is known to stimulate proteasome activity. In this study, three isomeric peptides were synthesised by [...] Read more.
L-carnosine (Car) is an endogenous dipeptide with significant potential in drug discovery for neurodegenerative diseases, while TAT1, a small arginine-rich peptide derived from the HIV-1 trans-activator protein (TAT), is known to stimulate proteasome activity. In this study, three isomeric peptides were synthesised by incorporating the Car moiety at the N-terminus, C-terminus, or central position of the TAT1 sequence. To differentiate these isomers, high-resolution and energy-resolved CID MS/MS experiments were conducted. The resulting MS/MS spectra showed a high degree of similarity among the peptides, predominantly characterised by fragment ion peaks arising from arginine-specific neutral losses. Energetic analysis was similarly inconclusive in resolving the isomers. However, Principal Component Analysis (PCA) enabled clear differentiation of the three peptides by considering the entire MS/MS spectra rather than focusing solely on precursor ion intensities or major fragment peaks. PCA loadings revealed distinct fragment ions for each peptide, albeit with lower intensities, providing insights into consecutive fragmentation patterns. Some of these specific peaks could also be attributed to scrambling during fragmentation. These results demonstrate the potential of PCA as a simple chemometric tool for semi-automated peak identification in complex MS/MS spectra. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)
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24 pages, 4051 KiB  
Article
Gold Nanoparticles as a Platform for Delivery of Immunogenic Peptides to THP-1 Derived Macrophages: Insights into Nanotoxicity
by Eduardo Zúñiga, Braulio Contreras-Trigo, Jorge Buchert, Fabián Sáez-Ahumada, Leonardo Hernández, Víctor Fica-León, Estefania Nova-Lamperti, Bostjan Kobe, Fanny Guzmán, Víctor Diaz-García, Enrique Guzmán-Gutiérrez and Patricio Oyarzún
Vaccines 2025, 13(2), 119; https://doi.org/10.3390/vaccines13020119 - 24 Jan 2025
Cited by 1 | Viewed by 1201
Abstract
Background: Peptide-based nanovaccines have emerged as a promising strategy for combating infectious diseases, as they overcome the low immunogenicity that is inherent to short epitope-containing synthetic peptides. Gold nanoparticles (AuNPs) present several advantages as peptide nanocarriers, but a deeper understanding of the design [...] Read more.
Background: Peptide-based nanovaccines have emerged as a promising strategy for combating infectious diseases, as they overcome the low immunogenicity that is inherent to short epitope-containing synthetic peptides. Gold nanoparticles (AuNPs) present several advantages as peptide nanocarriers, but a deeper understanding of the design criteria is paramount to accelerate the development of peptide-AuNPs nanoconjugates (p-AuNPs). Methods: Herein, we synthesized and characterized p-AuNPs of 23 nm (p-Au23) and 68 nm (p-Au68) with varying levels of peptide surface coverage and different peptide designs, investigating their effect on the cell viability (cell death and mitochondrial activity), cellular uptake, and cathepsin B activity in THP-1 macrophages. Results: p-Au23 proved no negative effect in the cell viability and high levels of nanoconjugate uptake, but p-Au68 induced strong toxicity to the cell line. The peptide sequences were successfully designed with spacer regions and a cell-penetrating peptide (pTAT) that enhanced cellular uptake and cathepsin B activity for p-Au23, while pTAT induced severe effects in the THP-1 viability (~40–60% cell death). Conclusions: These findings provide valuable insight into the design criteria of AuNPs and immunogenic peptides, along with nanotoxicity effects associated with AuNP size and surface charge in human monocyte-derived macrophages. Full article
(This article belongs to the Special Issue Innovations in Vaccine Technology)
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20 pages, 5540 KiB  
Article
Double Peptide-Functionalized Carboxymethyl Chitosan-Coated Liposomes Loaded with Dexamethasone as a Potential Strategy for Active Targeting Drug Delivery
by Loredana Iftode, Anca Niculina Cadinoiu, Delia Mihaela Raţă, Leonard Ionuț Atanase, Gabriela Vochiţa, Luminița Rădulescu, Marcel Popa and Daniela Gherghel
Int. J. Mol. Sci. 2025, 26(3), 922; https://doi.org/10.3390/ijms26030922 - 22 Jan 2025
Cited by 2 | Viewed by 1280
Abstract
Liposomes are intensively used as nanocarriers for biology, biochemistry, medicine, and in the cosmetics industry and their non-toxic and biocompatible nature makes these vesicles attractive systems for biomedical applications. Moreover, the conjugation of specific ligands to liposomes increases their cellular uptake and therapeutic [...] Read more.
Liposomes are intensively used as nanocarriers for biology, biochemistry, medicine, and in the cosmetics industry and their non-toxic and biocompatible nature makes these vesicles attractive systems for biomedical applications. Moreover, the conjugation of specific ligands to liposomes increases their cellular uptake and therapeutic efficiency. Considering these aspects, the aim of the present study was to obtain new formulations of cationic liposomes coated with dual-peptide functionalized carboxymethyl chitosan (CMCS) for the treatment of inner ear diseases. In order to achieve efficient active targeting and ensuring a high efficacy of the treatment, CMCS was functionalized with Tet1 peptide, to target specific ear cells, and TAT peptide, to ensure cellular penetration. Furthermore, dexamethasone phosphate was loaded as a model drug for the treatment of ear inflammation. The infrared spectroscopy confirmed the functionalization of CMCS with the two specific peptides. The mean diameter of the uncovered liposomes varied between 167 and 198 nm whereas the CMCS-coated liposomes ranged from 179 to 202 nm. TEM analysis showed the spherical shape and unilamellar structure of liposomes. The release efficiency of dexamethasone phosphate after 24 h from the uncoated liposomes was between 37 and 40% and it appeared that the coated liposomes modulated this release. The obtained results demonstrated that the liposomes are hemocompatible since, for a tested concentration of 100 µg/mL, the liposome suspension had a lysis of erythrocytes lower than 2.5% after 180 min of incubation. In addition, the peptide-functionalized CMCS-coated liposomes induced a non-significant effect on the viability of normal V79-4 cells after 48 h, at the highest doses. Values of 71.31% were recorded (CLCP-1), 77.28% (CLCP-2) and 74.36% (CLCP-3), correlated with cytotoxic effects of 28.69%, 22.72%, and 25.64%. Full article
(This article belongs to the Section Molecular Pharmacology)
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17 pages, 1600 KiB  
Article
Guanidines Conjugated with Cell-Penetrating Peptides: A New Approach for the Development of Antileishmanial Molecules
by João Victor Marcelino de Souza, Natalia C. S. Costa, Maria C. O. Arruda Brasil, Luana Ribeiro dos Anjos, Renata Priscila Barros de Menezes, Eduardo Henrique Zampieri, Jhonatan Santos de Lima, Angela Maria Arenas Velasquez, Luciana Scotti, Marcus Tullius Scotti, Marcia A. S. Graminha, Eduardo R. Pérez Gonzalez and Eduardo Maffud Cilli
Molecules 2025, 30(2), 264; https://doi.org/10.3390/molecules30020264 - 10 Jan 2025
Cited by 1 | Viewed by 1344
Abstract
Leishmaniasis is a neglected tropical disease caused by a protozoan of the genus Leishmania, which has visceral and cutaneous forms. The symptoms of leishmaniasis include high fever and weakness, and the cutaneous infection also causes lesions under the skin. The drugs used to [...] Read more.
Leishmaniasis is a neglected tropical disease caused by a protozoan of the genus Leishmania, which has visceral and cutaneous forms. The symptoms of leishmaniasis include high fever and weakness, and the cutaneous infection also causes lesions under the skin. The drugs used to treat leishmaniasis have become less effective due to the resistance mechanisms of the protozoa. In addition, the current compounds have low selectivity for the pathogen, leading to various side effects, which results in lower adherence to treatment. Various strategies were developed to solve this problem. The bioconjugation between natural compounds with antimicrobial activity and cell-penetrating peptides could alleviate the resistance and toxicity of current treatments. This work aims to conjugate the cell penetration peptide TAT to the guanidine GVL1. The GVL1-TAT bioconjugate exhibited leishmanicidal activity against Leishmania amazonensis and Leishmania infantum with a high selectivity index. In addition, the bioconjugate was more active against the intracellular enzyme CPP than the individual compounds. This target is very important for the viability and virulence of the parasite within the host cell. Docking studies confirmed the higher interaction of the conjugate with CPP and suggested that other proteins, such as trypanothione reductase, could be targeted. Thus, the data indicated that guanidines conjugated with cell-penetrating peptides could be a good approach for developing antileishmanial molecules. Full article
(This article belongs to the Section Chemical Biology)
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16 pages, 3190 KiB  
Article
Therapeutic Efficacy of Intranasal N-Acetyl-L-Cysteine with Cell-Penetrating Peptide-Modified Polymer Micelles on Neuropathic Pain in Partial Sciatic Nerve Ligation Mice
by Hiroshi Nango, Ai Takahashi, Naoto Suzuki, Takumi Kurano, Saia Sakamoto, Taiki Nagatomo, Toyofumi Suzuki, Takanori Kanazawa, Yasuhiro Kosuge and Hiroko Miyagishi
Pharmaceutics 2025, 17(1), 44; https://doi.org/10.3390/pharmaceutics17010044 - 1 Jan 2025
Cited by 2 | Viewed by 1747
Abstract
Background/Objectives: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal administration of N-acetyl-L-cysteine (NAC) combined with PEG-PCL-Tat (NAC/PPT) [...] Read more.
Background/Objectives: We previously demonstrated that the intranasal administration of cell-penetrating Tat peptide-modified carrier, PEG-PCL-Tat, improves drug delivery to the central nervous system. This study aimed to evaluate the potential of the post-onset intranasal administration of N-acetyl-L-cysteine (NAC) combined with PEG-PCL-Tat (NAC/PPT) for neuropathic pain. Methods: Neuropathic pain was induced by partial sciatic nerve ligation (PSNL) in mice. Mechanical allodynia was assessed using the von Frey test on days 11–14 post-ligation. NAC or NAC/PPT was intranasally administered after pain onset. Western blotting and immunohistochemistry were conducted to evaluate ionized calcium-binding adapter molecule 1 (Iba-1) expression and microglial activation in the spinal cord. Results: Mechanical allodynia was exacerbated 11 days after the ligation in PSNL mice. The intranasal administration of NAC alone prevented allodynia exacerbation but failed to provide a therapeutic effect against allodynia in PSNL mice. In contrast, NAC/PPT administration ameliorated PSNL-induced tactile allodynia, with maximum efficacy seen 13 and 14 days after ligation. Western blotting demonstrated that Iba-1 levels tended to increase in PSNL mice compared to controls. This trend of increased Iba-1 levels in PSNL mice was attenuated by the administration of NAC/PPT, but not by NAC alone. Immunohistochemistry revealed an increased number of Iba-1-stained microglia in the ipsilateral spinal cord of PSNL mice, which were significantly suppressed by the administration of NAC/PPT. Conclusions: These results suggest that the post-onset intranasal administration of NAC/PPT ameliorates mechanical allodynia by suppressing microglia induction and that intranasal delivery with PEG-PCL-Tat might be a useful tool for the pharmacological management of neuropathic pain. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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19 pages, 1632 KiB  
Article
New Conjugates of Vancomycin with Cell-Penetrating Peptides—Synthesis, Antimicrobial Activity, Cytotoxicity, and BBB Permeability Studies
by Jarosław Ruczyński, Katarzyna Prochera, Natalia Kaźmierczak, Katarzyna Kosznik-Kwaśnicka, Lidia Piechowicz, Piotr Mucha and Piotr Rekowski
Molecules 2024, 29(23), 5519; https://doi.org/10.3390/molecules29235519 - 22 Nov 2024
Cited by 2 | Viewed by 1912
Abstract
Vancomycin (Van) is a glycopeptide antibiotic commonly used as a last resort for treating life-threatening infections caused by multidrug-resistant bacterial strains, such as Staphylococcus aureus and Enterococcus spp. However, its effectiveness is currently limited due to the rapidly increasing number of drug-resistant clinical [...] Read more.
Vancomycin (Van) is a glycopeptide antibiotic commonly used as a last resort for treating life-threatening infections caused by multidrug-resistant bacterial strains, such as Staphylococcus aureus and Enterococcus spp. However, its effectiveness is currently limited due to the rapidly increasing number of drug-resistant clinical strains and its inherent cytotoxicity and poor penetration into cells and specific regions of the body, such as the brain. One of the most promising strategies to enhance its efficacy appears to be the covalent attachment of cell-penetrating peptides (CPPs) to the Van structure. In this study, a series of vancomycin conjugates with CPPs—such as TP10, Tat (47–57), PTD4, and Arg9—were designed and synthesized. These conjugates were tested for antimicrobial activity against four reference strains (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa) and two clinical drug-resistant strains: methicillin-resistant S. aureus and vancomycin-resistant E. faecium. In addition, cytotoxicity tests (using a human fibroblast cell line) and blood–brain barrier (BBB) permeability tests (using a parallel artificial membrane permeability assay—PAMPA-BBB assay) were conducted for selected compounds. Our research demonstrated that conjugation of Van with CPPs, particularly with Tat (47–57), Arg9, or TP10, significantly enhances its antimicrobial activity against Gram-positive bacteria such as S. aureus and Enterococcus spp., reduces its cytotoxicity, and improves its access to brain tissues. We conclude that these findings provide a strong foundation for the design of novel antimicrobial agents effective in treating infections caused by drug-resistant staphylococcal and enterococcal strains, while also being capable of crossing the BBB. Full article
(This article belongs to the Special Issue Chemical Biology of Antimicrobial Resistance, 2nd Edition)
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