TY - JOUR AU - Ugocsai, Melinda AU - Bársony, Anett AU - Varga, Réka A. AU - Gajda, Ámos AU - Vida, Noémi AU - Lajkó, Norbert AU - Rónaszéki, Benedek AU - Tóth, Gábor AU - Boros, Mihály AU - Érces, Dániel AU - Varga, Gabriella TI - Conjugation with Tris Decreases the Risk of Ketoprofen-Induced Mucosal Damage and Reduces Inflammation-Associated Methane Production in a Rat Model of Colitis JF - PHARMACEUTICS J2 - PHARMACEUTICS VL - 15 PY - 2023 IS - 9 PG - 17 SN - 1999-4923 DO - 10.3390/pharmaceutics15092329 UR - https://m2.mtmt.hu/api/publication/34145694 ID - 34145694 N1 - ISSN:1999-4923 AB - We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together with methane generation as a possible indicator of pro-inflammatory activation under this condition (approval number: V./148/2013). Whole-body methane production (photoacoustic spectroscopy) and serosal microcirculation (intravital videomicroscopy) were measured, and mucosal damage was assessed (conventional histology; in vivo laser-scanning endomicroscopy). Inflammatory markers were measured from tissue and blood samples. Colitis induced an inflammatory response, morphological colonic damage and increased methane output. Ket treatment lowered inflammatory activation and colonic mucosal injury, but macroscopic gastric bleeding and increased methane output were present. Ket-Tris reduced inflammatory activation, methane emission and colonic mucosal damage, without inducing gastric injury. Conjugation with Tris reduces the GI side effects of Ket and still decreases the inflammatory response in experimental colitis. Methane output correlates with the mucosal inflammatory response and non-invasively demonstrates the effects of anti-inflammatory treatments. LA - English DB - MTMT ER - TY - JOUR AU - Tarjányi, Tamás AU - Bogár, Ferenc AU - Minárovits, János AU - Gajdács, Márió AU - Tóth, Zsolt TI - Interaction of biomolecules with anatase, rutile and amorphous TiO2 surfaces: A molecular dynamics study JF - PLOS ONE J2 - PLOS ONE VL - 18 PY - 2023 IS - 9 PG - 19 SN - 1932-6203 DO - 10.1371/journal.pone.0289467 UR - https://m2.mtmt.hu/api/publication/34127552 ID - 34127552 N1 - Funding Agency and Grant Number: University of Szeged [GINOP-2.3.2-15-2016-00011]; [6103] Funding text: This work was supported by the grant GINOP-2.3.2-15-2016-00011, in the initial phase and by the University of Szeged Open Access Fund (Grant number: 6103). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AB - The adhesion of biomolecules to dental and orthopedic implants is a fundamental step in the process of osseointegration. Short peptide motifs, such as RGD or KRSR, carried by extracellular matrix proteins or coated onto implant surfaces, accelerate cell adhesion and tissue formation. For this reason, understanding the binding mechanisms of adhesive peptides to oxidized surfaces of titanium implants is of paramount importance. We performed molecular dynamics simulations to compare the adhesion properties of 6 peptides, including the tripeptide RGD, its variants KGD and LGD, as well as the tetrapeptide KRSR, its variant LRSR and its truncated version RSR, on anatase, rutile, and amorphous titanium dioxide (TiO 2 ) surfaces. The migration of these molecules from the water phase to the surface was simulated in an aqueous environment. Based on these simulations, we calculated the residence time of each peptide bound to the three different TiO 2 structures. It was found that the presence of an N-terminal lysine or arginine amino acid residue resulted in more efficient surface binding. A pulling simulation was performed to detach the adhered molecules. The maximum pulling force and the binding energy were determined from the results of these simulations. The tri- and tetrapeptides had slightly greater adhesion affinity to the amorphous and anatase structure than to rutile in general, however specific surface and peptide binding characters could be detected. The binding energies obtained from our simulations allowed us to rank the adhesion strengths of the studied peptides. LA - English DB - MTMT ER - TY - JOUR AU - Patkó, Evelin Viktória AU - Szabó, Edina AU - Váczy, Alexandra AU - Molitor, Dorottya AU - Tari, Eniko AU - Li, Lina AU - Csutak, Adrienne AU - Tóth, Gábor AU - Reglődi, Dóra AU - Atlasz, Tamás TI - Protective Effects of Pituitary Adenylate-Cyclase-Activating Polypeptide on Retinal Vasculature and Molecular Responses in a Rat Model of Moderate Glaucoma JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 17 PG - 14 SN - 1661-6596 DO - 10.3390/ijms241713256 UR - https://m2.mtmt.hu/api/publication/34117220 ID - 34117220 N1 - Export Date: 3 April 2024 AB - Despite the high probability of glaucoma-related blindness, its cause is not fully understood and there is no efficient therapeutic strategy for neuroprotection. Vascular factors have been suggested to play an important role in glaucoma development and progression. Previously, we have proven the neuroprotective effects of pituitary adenylate-cyclase-activating polypeptide (PACAP) eye drops in an inducible, microbeads model in rats that is able to reproduce many clinically relevant features of human glaucoma. In the present study, we examined the potential protective effects of PACAP1-38 on the retinal vasculature and the molecular changes in hypoxia. Ocular hypertension was induced by injection of microbeads into the anterior chamber, while control rats received PBS. PACAP dissolved in vehicle (1 µg/drop) or vehicle treatment was started one day after the injections for four weeks three times a day. Retinal degeneration was assessed with optical coherence tomography (OCT), and vascular and molecular changes were assessed by immunofluorescence labeling. HIF1-α and VEGF-A protein levels were measured by Western blot. OCT images proved severe retinal degeneration in the glaucomatous group, while PACAP1-38 eye drops had a retinoprotective effect. Vascular parameters were deteriorated and molecular analysis suggested hypoxic conditions in glaucoma. PACAP treatment exerted a positive effect against these alterations. In summary, PACAP could prevent the severe damage to the retina and its vasculature induced by ocular hypertension in a microbeads model. LA - English DB - MTMT ER - TY - JOUR AU - Bartus, Éva AU - Tököli, Attila AU - Mag, Beáta Zsófia AU - Bajcsi, Áron AU - Kecskeméti, Gábor AU - Wéber, Edit AU - Kele, Zoltán AU - Fenteany, Gabriel AU - Martinek, Tamás TI - Light-Fueled Primitive Replication and Selection in Biomimetic Chemical Systems JF - JOURNAL OF THE AMERICAN CHEMICAL SOCIETY J2 - J AM CHEM SOC VL - 145 PY - 2023 IS - 24 SP - 13371 EP - 13383 PG - 13 SN - 0002-7863 DO - 10.1021/jacs.3c03597 UR - https://m2.mtmt.hu/api/publication/34043894 ID - 34043894 N1 - Department of Medical Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary ELKH-SZTE Biomimetic Systems Research Group, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Institute of Genetics, Biological Research Centre, Temesvári krt. 62, Szeged, H-6726, Hungary Cited By :2 Export Date: 17 April 2024 CODEN: JACSA Correspondence Address: Martinek, T.A.; Department of Medical Chemistry, Dóm tér 8, Hungary; email: martinek.tamas@med.u-szeged.hu AB - The concept of chemically evolvable replicators is centralto abiogenesis.Chemical evolvability requires three essential components: energy-harvestingmechanisms for nonequilibrium dissipation, kinetically asymmetricreplication and decomposition pathways, and structure-dependent selectivetemplating in the autocatalytic cycles. We observed a UVA light-fueledchemical system displaying sequence-dependent replication and replicatordecomposition. The system was constructed with primitive peptidicfoldamer components. The photocatalytic formation-recombinationcycle of thiyl radicals was coupled with the molecular recognitionsteps in the replication cycles. Thiyl radical-mediated chain reactionwas responsible for the replicator death mechanism. The competingand kinetically asymmetric replication and decomposition processesled to light intensity-dependent selection far from equilibrium. Here,we show that this system can dynamically adapt to energy influx andseeding. The results highlight that mimicking chemical evolution isfeasible with primitive building blocks and simple chemical reactions. LA - English DB - MTMT ER - TY - JOUR AU - Váradi, Györgyi AU - Kele, Zoltán AU - Czajlik, András AU - Borics, Attila AU - Bende, Gábor AU - Papp, Csaba Gergő AU - Rákhely, Gábor AU - Tóth, Gábor AU - Batta, Gyula AU - Galgóczi, László Norbert TI - Hard nut to crack: Solving the disulfide linkage pattern of the Neosartorya (Aspergillus) fischeri antifungal protein 2 JF - PROTEIN SCIENCE J2 - PROTEIN SCI VL - 32 PY - 2023 IS - 7 PG - 13 SN - 0961-8368 DO - 10.1002/pro.4692 UR - https://m2.mtmt.hu/api/publication/34043893 ID - 34043893 N1 - Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary Department of Organic Chemistry, Faculty of Science and Technology, University of Debrecen, Debrecen, Hungary Department of Biochemistry, Institute of Biochemistry and Molecular Biology, Semmelweis University, Budapest, Hungary Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary Department of Biotechnology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary Department of Microbiology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary Fungal Genomics and Evolution Lab, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary Export Date: 11 August 2023 CODEN: PRCIE Correspondence Address: Váradi, G.; Department of Medical Chemistry, Dóm tér 8, Hungary; email: varadi.gyorgyi@med.u-szeged.hu Correspondence Address: Galgóczy, L.; Department of Biotechnology, Közép fasor 52, Hungary; email: galgoczi@bio.u-szeged.hu Chemicals/CAS: disulfide, 16734-12-6; Antifungal Agents; Disulfides AB - As a consequence of the fast resistance spreading, a limited number of drugs are available to treat fungal infections. Therefore, there is an urgent need to develop new antifungal treatment strategies. The features of a disulfide bond-stabilized antifungal protein, NFAP2 secreted by the mold Neosartorya (Aspergillus) fischeri render it to be a promising template for future protein-based antifungal drug design, which requires knowledge about the native disulfide linkage pattern as it is one of the prerequisites for biological activity. However, in the lack of tryptic and chymotryptic proteolytic sites in the ACNCPNNCK sequence, the determination of the disulfide linkage pattern of NFAP2 is not easy with traditional mass spectrometry-based methods. According to in silico predictions working with a preliminary nuclear magnetic resonance (NMR) solution structure, two disulfide isomers of NFAP2 (abbacc and abbcac) were possible. Both were chemically synthesized; and comparative reversed-phase high-performance liquid chromatography, electronic circular dichroism and NMR spectroscopy analyses, and antifungal susceptibility and efficacy tests indicated that the abbcac is the native pattern. This knowledge allowed rational modification of NAFP2 to improve the antifungal efficacy and spectrum through the modulation of the evolutionarily conserved gamma-core region, which is responsible for the activity of several antimicrobial peptides. Disruption of the steric structure of NFAP2 upon gamma-core modification led to the conclusions that this motif may affect the formation of the biologically active three-dimensional structure, and that the gamma-core modulation is not an efficient tool to improve the antifungal efficacy or to change the antifungal spectrum of NFAP2. LA - English DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Szűcs, Mária AU - Bogár, Ferenc TI - Alzheimer-kór: le tudjuk-e lassítani a betegséget, lesz-e oki terápia? JF - BIOKÉMIA: A MAGYAR BIOKÉMIAI EGYESÜLET FOLYÓIRATA J2 - BIOKÉMIA VL - 47 PY - 2023 IS - 2 SP - 10 EP - 29 PG - 20 SN - 0133-8455 UR - https://m2.mtmt.hu/api/publication/34030642 ID - 34030642 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Tököli, Attila AU - Bodnár, Brigitta AU - Bogár, Ferenc AU - Paragi, Gábor AU - Hetényi, Anasztázia AU - Bartus, Éva AU - Wéber, Edit AU - Hegedüs, Zsófia AU - Szabó, Zoltán AU - Kecskeméti, Gábor AU - Szakonyi, Gerda AU - Martinek, Tamás TI - Structural Adaptation of the Single-Stranded DNA-Binding Protein C-Terminal to DNA Metabolizing Partners Guides Inhibitor Design JF - PHARMACEUTICS J2 - PHARMACEUTICS VL - 15 PY - 2023 IS - 4 PG - 17 SN - 1999-4923 DO - 10.3390/pharmaceutics15041032 UR - https://m2.mtmt.hu/api/publication/33712712 ID - 33712712 N1 - Department of Medical Chemistry, University of Szeged, Szeged, H6720, Hungary ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), Szeged, H6720, Hungary Institute of Physics, University of Pécs, Pécs, H7624, Hungary Department of Theoretical Physics, University of Szeged, Szeged, H6720, Hungary Institute of Pharmaceutical Analysis, University of Szeged, Szeged, H6720, Hungary Export Date: 8 September 2023 Correspondence Address: Martinek, T.A.; Department of Medical Chemistry, Hungary; email: martinek.tamas@med.u-szeged.hu AB - Single-stranded DNA-binding protein (SSB) is a bacterial interaction hub and an appealing target for antimicrobial therapy. Understanding the structural adaptation of the disordered SSB C-terminus (SSB-Ct) to DNA metabolizing enzymes (e.g., ExoI and RecO) is essential for designing high-affinity SSB mimetic inhibitors. Molecular dynamics simulations revealed the transient interactions of SSB-Ct with two hot spots on ExoI and RecO. The residual flexibility of the peptide–protein complexes allows adaptive molecular recognition. Scanning with non-canonical amino acids revealed that modifications at both termini of SSB-Ct could increase the affinity, supporting the two-hot-spot binding model. Combining unnatural amino acid substitutions on both segments of the peptide resulted in enthalpy-enhanced affinity, accompanied by enthalpy–entropy compensation, as determined by isothermal calorimetry. NMR data and molecular modeling confirmed the reduced flexibility of the improved affinity complexes. Our results highlight that the SSB-Ct mimetics bind to the DNA metabolizing targets through the hot spots, interacting with both of segments of the ligands. LA - English DB - MTMT ER - TY - JOUR AU - Penke, Botond AU - Szűcs, Mária AU - Bogár, Ferenc TI - New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 6 PG - 23 SN - 1661-6596 DO - 10.3390/ijms24065383 UR - https://m2.mtmt.hu/api/publication/33702944 ID - 33702944 N1 - ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, GINOP-2.3.2-15-2016-00034, GINOP-2.3.2-15-2016-00060 Funding text 1: This research was funded by National Research Development and Innovation Office (NKFIH), grant numbers GINOP-2.3.2-15-2016-00060 and GINOP-2.3.2-15-2016-00034. AB - Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60–80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research. LA - English DB - MTMT ER - TY - JOUR AU - Váradi, Györgyi AU - Batta, Gyula AU - Galgóczi, László Norbert AU - Hajdu, Dorottya Zsuzsanna AU - Fizil, Ádám AU - Czajlik, András AU - Virágh, Máté AU - Kele, Zoltán AU - Meyer, Vera AU - Jung, Sascha AU - Marx, Florentine AU - Tóth, Gábor TI - Confirmation of the Disulfide Connectivity and Strategies for Chemical Synthesis of the Four-Disulfide-Bond-Stabilized Aspergillus giganteus Antifungal Protein, AFP JF - JOURNAL OF NATURAL PRODUCTS J2 - J NAT PROD VL - 86 PY - 2023 IS - 4 SP - 782 EP - 790 PG - 9 SN - 0163-3864 DO - 10.1021/acs.jnatprod.2c00954 UR - https://m2.mtmt.hu/api/publication/33676645 ID - 33676645 N1 - Funding Agency and Grant Number: Hungarian National Research, Development [TKP2021-EGA-32]; Innovation Office-NKFIH; Hungarian National Research, Development and Innovation Office-NKFIH [FK 134343]; Austrian Science Fund [392923329]; Deutsche Forschungsgemeinschaft (DFG); [I1644-B20] Funding text: We thank D. Bratschun-Khan for her technical assistance. G.V. and G.K.T. were supported by the TKP2021-EGA-32 fund of the Hungarian National Research, Development, and Innovation Office-NKFIH, and L.G. was financed by the Hungarian National Research, Development and Innovation Office-NKFIH, FK 134343 project. This work was financed by the Austrian Science Fund (FWF I1644-B20) to F.M. and by the Deutsche Forschungsgemeinschaft (DFG, GRK2473 Bioactive Peptides project number 392923329) to S.J. and V.M. AB - Emerging fungal infections require new, more efficient antifungal agents and therapies. AFP, a protein from Aspergillus giganteus with four disulfide bonds, is a promising candidate because it selectively inhibits the growth of filamentous fungi. In this work, the reduced form of AFP was prepared using native chemical ligation. The native protein was synthesized via oxidative folding with uniform protection for cysteine thiols. AFP's biological activity depends heavily on the pattern of natural disulfide bonds. Enzymatic digestion and MS analysis provide proof for interlocking disulfide topology (abcdabcd) that was previously assumed. With this knowledge, a semi-orthogonal thiol protection method was designed. By following this strategy, out of a possible 105, only 6 disulfide isomers formed and 1 of them proved to be identical with the native protein. This approach allows the synthesis of analogs for examining structure-activity relationships and, thus, preparing AFP variants with higher antifungal activity. LA - English DB - MTMT ER - TY - JOUR AU - Howan, Dian Herlinda Octorina AU - Jenei, Sándor AU - Szolomájer, János AU - Endre, Gabriella AU - Kondorosi, Éva AU - Tóth, Gábor TI - Enhanced Antibacterial Activity of Substituted Derivatives of NCR169C Peptide JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 3 PG - 13 SN - 1661-6596 DO - 10.3390/ijms24032694 UR - https://m2.mtmt.hu/api/publication/33611580 ID - 33611580 N1 - Export Date: 18 April 2023 AB - Medicago truncatula in symbiosis with its rhizobial bacterium partner produces more than 700 nodule-specific cysteine-rich (NCR) peptides with diverse physicochemical properties. Most of the cationic NCR peptides have antimicrobial activity and the potential to tackle antimicrobial resistance with their novel modes of action. This work focuses on the antibacterial activity of the NCR169 peptide derivatives as we previously demonstrated that the C-terminal sequence of NCR169 (NCR169C17–38) has antifungal activity, affecting the viability, morphology, and biofilm formation of various Candida species. Here, we show that NCR169C17–38 and its various substituted derivatives are also able to kill ESKAPE pathogens such as Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. The replacement of the two cysteines with serines enhanced the antimicrobial activity against most of the tested bacteria, indicating that the formation of a disulfide bridge is not required. As tryptophan can play role in the interaction with bacterial membranes and thus in antibacterial activity, we replaced the tryptophans in the NCR169C17–38C12,17/S sequence with various modified tryptophans, namely 5-methyl tryptophan, 5-fluoro tryptophan, 6-fluoro tryptophan, 7-aza tryptophan, and 5-methoxy tryptophan, in the synthesis of NCR169C17–38C12,17/S analogs. The results demonstrate that the presence of modified fluorotryptophans can significantly enhance the antimicrobial activity without notable hemolytic effect, and this finding could be beneficial for the further development of new AMPs from the members of the NCR peptide family. LA - English DB - MTMT ER -