TY - JOUR AU - Hőgye, Fanni AU - Farkas, László Bence AU - Balogh, Álex Kálmán AU - Szilágyi, László AU - Alnukari, Samar AU - Bajza, István AU - Borbás, Anikó AU - Fehér, Krisztina AU - Tóthné Illyés, Tünde Zita AU - Timári, István TI - Saturation Transfer Difference NMR and Molecular Docking Interaction Study of Aralkyl-Thiodigalactosides as Potential Inhibitors of the Human-Galectin-3 Protein JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 3 PG - 18 SN - 1661-6596 DO - 10.3390/ijms25031742 UR - https://m2.mtmt.hu/api/publication/34567562 ID - 34567562 AB - Human Galectin-3 (hGal-3) is a protein that selectively binds to β-galactosides and holds diverse roles in both normal and pathological circumstances. Therefore, targeting hGal-3 has become a vibrant area of research in the pharmaceutical chemistry. As a step towards the development of novel hGal-3 inhibitors, we synthesized and investigated derivatives of thiodigalactoside (TDG) modified with different aromatic substituents. Specifically, we describe a high-yielding synthetic route of thiodigalactoside (TDG); an optimized procedure for the synthesis of the novel 3,3′-di-O-(quinoline-2-yl)methyl)-TDG and three other known, symmetric 3,3′-di-O-TDG derivatives ((naphthalene-2yl)methyl, benzyl, (7-methoxy-2H-1-benzopyran-2-on-4-yl)methyl). In the present study, using competition Saturation Transfer Difference (STD) NMR spectroscopy, we determined the dissociation constant (Kd) of the former three TDG derivatives produced to characterize the strength of the interaction with the target protein (hGal-3). Based on the Kd values determined, the (naphthalen-2-yl)methyl, the (quinolin-2-yl)methyl and the benzyl derivatives bind to hGal-3 94, 30 and 24 times more strongly than TDG. Then, we studied the binding modes of the derivatives in silico by molecular docking calculations. Docking poses similar to the canonical binding modes of well-known hGal-3 inhibitors have been found. However, additional binding forces, cation–π interactions between the arginine residues in the binding pocket of the protein and the aromatic groups of the ligands, have been established as significant features. Our results offer a molecular-level understanding of the varying affinities observed among the synthesized thiodigalactoside derivatives, which can be a key aspect in the future development of more effective ligands of hGal-3. LA - English DB - MTMT ER - TY - JOUR AU - Gönczi, Mónika AU - Teixeira, João M. C. AU - Barrera-Vilarmau, Susana AU - Mediani, Laura AU - Antoniani, Francesco AU - Nagy, Tamás Milán AU - Fehér, Krisztina AU - Ráduly, Zsolt AU - Ambrus, Viktor Attila AU - Tőzsér, József AU - Barta, Endre AU - E Kövér, Katalin AU - Csernoch, László AU - Carra, Serena AU - Fuxreiter, Mónika TI - Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 14 PY - 2023 PG - 13 SN - 2041-1723 DO - 10.1038/s41467-023-37017-7 UR - https://m2.mtmt.hu/api/publication/33693788 ID - 33693788 AB - During muscle cell differentiation, the alternatively spliced, acidic β-domain potentiates transcription of Myocyte-specific Enhancer Factor 2 (Mef2D). Sequence analysis by the FuzDrop method indicates that the β-domain can serve as an interaction element for Mef2D higher-order assembly. In accord, we observed Mef2D mobile nuclear condensates in C2C12 cells, similar to those formed through liquid-liquid phase separation. In addition, we found Mef2D solid-like aggregates in the cytosol, the presence of which correlated with higher transcriptional activity. In parallel, we observed a progress in the early phase of myotube development, and higher MyoD and desmin expression. In accord with our predictions, the formation of aggregates was promoted by rigid β-domain variants, as well as by a disordered β-domain variant, capable of switching between liquid-like and solid-like higher-order states. Along these lines, NMR and molecular dynamics simulations corroborated that the β-domain can sample both ordered and disordered interactions leading to compact and extended conformations. These results suggest that β-domain fine-tunes Mef2D higher-order assembly to the cellular context, which provides a platform for myogenic regulatory factors and the transcriptional apparatus during the developmental process. LA - English DB - MTMT ER - TY - JOUR AU - Hadháziné Raics, Mária AU - Balogh, Álex Kálmán AU - Kishor, Chandan AU - Timári, István AU - Medrano, Francisco J. AU - Romero, Antonio AU - Go, Rob Marc AU - Blanchard, Helen AU - Szilágyi, László AU - E Kövér, Katalin AU - Fehér, Krisztina TI - Investigation of the Molecular Details of the Interactions of Selenoglycosides and Human Galectin-3 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 5 PG - 17 SN - 1661-6596 DO - 10.3390/ijms23052494 UR - https://m2.mtmt.hu/api/publication/32707268 ID - 32707268 N1 - Funding details: ÚNKP-21-4-DE-165 Funding details: Magyar Tudományos Akadémia, MTA, BO/00372/20/7, ÚNKP-21-5-DE-471 Funding details: European Regional Development Fund, ERDF, GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, NN 128368, PD 135034 Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA, BO/004333/18/7 Funding details: Innovációs és Technológiai Minisztérium Funding text 1: Funding: Our studies were supported by the National Research, Development and Innovation Office of Hungary (grant numbers: NN 128368 (to L.S.Z. and K.E.K.) and PD 135034 (to I.T.) and co-financed by the European Regional Development Fund (projects GINOP-2.3.3-15-2016-00004 and GINOP-2.3.2-15-2016-00008). The research of I.T. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the ÚNKP-21-5-DE-471 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. K.F. acknowledges the support of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (ÚNKP-21-4-DE-165 Bolyai+). We acknowledge the Governmental Information Technology Development Agency for awarding us access to supercomputing resources based in Debrecen, Hungary. AB - Human galectin-3 (hGal-3) is involved in a variety of biological processes and is implicated in wide range of diseases. As a result, targeting hGal-3 for clinical applications has become an intense area of research. As a step towards the development of novel hGal-3 inhibitors, we describe a study of the binding of two Se-containing hGal-3 inhibitors, specifically that of di(β-Dgalactopyranosyl)selenide (SeDG), in which two galactose rings are linked by one Se atom and a di(β-D-galactopyranosyl)diselenide (DSeDG) analogue with a diseleno bond between the two sugar units. The binding affinities of these derivatives to hGal-3 were determined by 15N-1H HSQC NMR spectroscopy and fluorescence anisotropy titrations in solution, indicating a slight decrease in the strength of interaction for SeDG compared to thiodigalactoside (TDG), a well-known inhibitor of hGal-3, while DSeDG displayed a much weaker interaction strength. NMR and FA measurements showed that both seleno derivatives bind to the canonical S face site of hGal-3 and stack against the conserved W181 residue also confirmed by X-ray crystallography, revealing canonical properties of the interaction. The interaction with DSeDG revealed two distinct binding modes in the crystal structure which are in fast exchange on the NMR time scale in solution, explaining a weaker interaction with hGal-3 than SeDG. Using molecular dynamics simulations, we have found that energetic contributions to the binding enthalpies mainly differ in the electrostatic interactions and in polar solvation terms and are responsible for weaker binding of DSeDG compared to SeDG. Selenium-containing carbohydrate inhibitors of hGal-3 showing canonical binding modes offer the potential of becoming novel hydrolytically stable scaffolds for a new class of hGal-3 inhibitors. LA - English DB - MTMT ER - TY - JOUR AU - Timári, István AU - Balla, Sára AU - Fehér, Krisztina AU - E Kövér, Katalin AU - Szilágyi, László TI - 77Se-Enriched Selenoglycoside Enables Significant Enhancement in NMR Spectroscopic Monitoring of Glycan–Protein Interactions JF - PHARMACEUTICS J2 - PHARMACEUTICS VL - 14 PY - 2022 IS - 1 PG - 8 SN - 1999-4923 DO - 10.3390/pharmaceutics14010201 UR - https://m2.mtmt.hu/api/publication/32603044 ID - 32603044 N1 - Funding details: NN 128368, PD 135034 Funding details: Magyar Tudományos Akadémia, MTA, BO/00372/20/7, ÚNKP-21-5-DE-471 Funding details: European Regional Development Fund, ERDF, GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004 Funding details: Innovációs és Technológiai Minisztérium Funding text 1: Funding: Our studies were supported by the National Research, Development, and Innovation Office of Hungary (grant numbers: NN 128368 (to L.S. and K.E.K.) and PD 135034 (to I.T.)) and co-financed by the European Regional Development Fund (projects GINOP-2.3.3-15-2016-00004 and GINOP-2.3.2-15-2016-00008). The research of I.T. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the ÚNKP-21-5-DE-471 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development, and Innovation Fund. AB - Detailed investigation of ligand–protein interactions is essential for better understanding of biological processes at the molecular level. Among these binding interactions, the recognition of glycans by lectins is of particular importance in several diseases, such as cancer; therefore, inhibition of glycan-lectin/galectin interactions represents a promising perspective towards developing therapeutics controlling cancer development. The recent introduction of 77Se NMR spectroscopy for monitoring the binding of a selenoglycoside to galectins prompted interest to optimize the sensitivity by increasing the 77Se content from the natural 7.63% abundance to 99%. Here, we report a convenient synthesis of 77Se-enriched selenodigalactoside (SeDG), which is a potent ligand of the medically relevant human galectin-3 protein, and proof of the expected sensitivity gain in 2D 1H, 77Se correlation NMR experiments. Our work opens perspectives for adding isotopically enriched selenoglycans for rapid monitoring of lectin-binding of selenated as well as non-selenated ligands and for ligand screening in competition experiments. LA - English DB - MTMT ER - TY - JOUR AU - Toth, Barna AU - Fehér, Krisztina TI - Conformation of Immune Stimulatory Single Stranded DNA by Biomolecular Simulations and NMR JF - BIOPHYSICAL JOURNAL J2 - BIOPHYS J VL - 120 PY - 2021 IS - 3 SP - 218A EP - 218A PG - 1 SN - 0006-3495 DO - 10.1021/scimeetings.1c01247 UR - https://m2.mtmt.hu/api/publication/32235245 ID - 32235245 N1 - 1059-Poster AB - Immunotherapies require novel type of delivery systems with specifically tailored adjuvants to activate immune responses. Among immune stimulators of microbial origin, oligodeoxynucleotides (ODNs) represent the most advanced potential adjuvants. ODNs are unmethylated single stranded DNA (ssDNA) sequences with CpG-motifs, which are able to activate the innate immune system by binding to TLR9 receptors. Adjuvant effects are optimized by maintaining ODNs and vaccine antigens in close proximity, which can be achieved by loading the immune stimulator and the antigen cargo to an appropriate carrier such as inorganic nanoparticles. Immobilisation of ODN immune stimulators onto the surface of nanoparticles while maintaining multivalent presentation to TLR9 receptors requires knowledge of their conformational properties. De novo modelling of ssDNA conformation, opposed to that of double stranded DNA, is challenging due to multiple reasons. ssDNA lacks stable structures and can only be described as an ensemble of interconverting conformations, thus methods for adequate sampling of the conformational space need to be applied. Force fields for simulation of DNAs were, however, developed by testing them mainly on duplex DNA and their ability to reproduce conformations of ssDNA is unclear. In this regard, modelling of ssDNA likely face similar challenges as modelling of Intrinsically Disordered Proteins. We set out to test the accuracy of existing DNA force fields using atomistic molecular dynamics (MD) simulations and NMR spectroscopy. Translational diffusion coefficients were obtained from diffusion experiments and compared to translational diffusion coefficients, radius of gyration and end-to-end distances calculated from MD simulations. Furthermore, we analysed secondary structure formation and descriptors of dynamic behaviour. Outcome of comparisons for different DNA force fields are discussed. LA - English DB - MTMT ER - TY - JOUR AU - Balogh, Gábor AU - Gyöngyösi, Tamás AU - Timári, István AU - Herczeg, Mihály AU - Borbás, Anikó AU - Sadiq, S. Kashif AU - Fehér, Krisztina AU - E Kövér, Katalin TI - Conformational Analysis of Heparin-Analogue Pentasaccharides by Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulations JF - JOURNAL OF CHEMICAL INFORMATION AND MODELING J2 - J CHEM INF MODEL VL - 61 PY - 2021 IS - 6 SP - 2926 EP - 2936 PG - 11 SN - 1549-9596 DO - 10.1021/acs.jcim.1c00200 UR - https://m2.mtmt.hu/api/publication/32217410 ID - 32217410 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [NKFI NN 128368, NKFI PD 135034]; European Regional Development FundEuropean Commission [GINOP-2.3.3-15-2016-00004, GINOP2.3.2-15-2016-00044]; Hungarian Scientific Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA-106294]; Talentum Foundation" of Gedeon Richter PLC; New National Excellence Program of The Ministry of Human Capacities [UNKP-18-3]; Premium Postdoctoral Program of the Hungarian Academy of Sciences [PPD 461038]; Mizutani Foundation [150091]; Volkswagen Foundation "Experiment! Funding Initiative" [93874]; Klaus Tschira Foundation; Marie Curie Career Integration Grant [303917 PGNINNATE]; Research Foundation-FlandersFWO [1508414N, 1525517N]; Hungarian Academy of SciencesHungarian Academy of Sciences [BO/004333/18/7]; New National Excellence Program of Debrecen University [UNKP-20-4-DE-165]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences [BO/00372/20/7]; National Research, Development and Innovation Fund [UNKP-20-5-DE-262]; Governmental Information Technology Development Agency Funding text: This work is dedicated to the memory of our colleague and dear friend, Dr. Istvan Komaromi. This research was supported by the National Research, Development and Innovation Office of Hungary (grant numbers: NKFI NN 128368 and NKFI PD 135034), co-financed by the European Regional Development Fund (projects GINOP-2.3.3-15-2016-00004 and GINOP2.3.2-15-2016-00044) and by the Hungarian Scientific Research Fund (OTKA-106294). B.G. is a recipient of a scholarship from "Talentum Foundation" of Gedeon Richter PLC. T.Gy. acknowledges the U ' NKP-18-3 New National Excellence Program of The Ministry of Human Capacities. M.H. is grateful for the support of the Premium Postdoctoral Program of the Hungarian Academy of Sciences (PPD 461038). A.B. acknowledges the support of the Mizutani Foundation for Glycoscience (150091). S.K.S. acknowledges support from the Volkswagen Foundation "Experiment! Funding Initiative" Grant No. 93874 and from the Klaus Tschira Foundation. K.F. acknowledges the support of the Marie Curie Career Integration Grant (303917 PGNINNATE), the Research Grant from the Research Foundation-Flanders (1508414N and 1525517N), Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7), and the New National Excellence Program of Debrecen University (U ' NKP-20-4-DE-165 Bolyai +). I.T. acknowledges the support of the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the U ' NKP-20-5-DE-262 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. We acknowledge Governmental Information Technology Development Agency for awarding us access to the supercomputing resources based in Debrecen, Hungary. LA - English DB - MTMT ER - TY - JOUR AU - Sajtos, Zsófi AU - Fehér, Milán AU - Molnár, Áron AU - Stündl, László AU - Nagyné Naszályi, Lívia AU - Martins, José C. AU - Harangi, Sándor AU - Magyar, István AU - Fehér, Krisztina AU - Baranyai, Edina TI - The retention of Zr from potential therapeutic silica-zirconia core-shell nanoparticles in aquatic organisms JF - ENVIRONMENTAL NANOTECHNOLOGY MONITORING AND MANAGEMENT J2 - ENVIRON NANOTECH MONITOR MANAG VL - 16 PY - 2021 PG - 10 SN - 2215-1532 DO - 10.1016/j.enmm.2021.100572 UR - https://m2.mtmt.hu/api/publication/32201080 ID - 32201080 N1 - Correspondence Address: Fehér, K.; Molecular Recognition and Interaction Research Group, Egyetem tér 1, Hungary; email: feher.krisztina@science.unideb Funding details: Agilent Technologies Funding details: Horizon 2020 Framework Programme, H2020 Funding details: H2020 Marie Skłodowska-Curie Actions, MSCA, 703374 Funding details: European Commission, EC Funding details: Magyar Tudományos Akadémia, MTA, BO/004333/18/7 Funding details: Horizon 2020 Funding details: European Regional Development Fund, ERDF, GINOP-2.3.2-15-2016-00008 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, NKFI/OTKA NN 128368 Funding details: Vlaamse regering Funding text 1: The research was supported by the EU and co-financed by the European Regional Development Fund under the project GINOP-2.3.2-15-2016-00008. We acknowledge the Agilent Technologies, Inc. and the Novo-Lab Ltd. (Hungary) for providing the MP-AES 4200 and the ICP-OES 5100 instruments for the elemental analysis. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 703374. E.D. acknowledges FWO-Vlaanderen for a fellowship (FWO-SB fellowship). K.F. acknowledges the support of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences ( BO/004333/18/7 ) and the New National Excellence Program of Debrecen University (ÚNKP-20-4 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368 ). Funding text 2: The research was supported by the EU and co-financed by the European Regional Development Fund under the project GINOP-2.3.2-15-2016-00008. We acknowledge the Agilent Technologies, Inc. and the Novo-Lab Ltd. (Hungary) for providing the MP-AES 4200 and the ICP-OES 5100 instruments for the elemental analysis. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 703374. E.D. acknowledges FWO-Vlaanderen for a fellowship (FWO-SB fellowship). K.F. acknowledges the support of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (ÚNKP-20-4 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368). AB - Model experiments under laboratory conditions were carried out to assess the accumulation tendency of Zr from a silica-zirconia core-shell nanoparticles, synthesised for the assay. Acute exposition tests were conducted with Daphnia magna and Danio rerio and the accumulation tendency of the nano and the molecular form was compared. Significant elevation of Zr was found in the tissue of the test organisms treated by the NP compared to the control, however, the retention of zebrafish was lower than that of the daphnids. Increased level of bioconcentration factor and the strong correlation of the redundancy analysis data suggest accumulation tendency in D. magna, yet long-term experiments are required to prove and further assess the environmental risk of food-chain bioconcentration. The BCF results were under the REACH limit for the D. rerio groups indicating the low short-term accumulation tendency of Zr from the NP. However, Zr level was significantly higher in zebrafish individuals originating from the SiO2@ZrO2 NP exposed treatments compared to the groups supplemented by the same concentration of ZrOCl2, which did not result in the elevation of Zr in fish tissue. The trace element homeostasis of D. rerio was not affected by the acute SiO2@ZrO2 NP exposition and no lethality occurred. LA - English DB - MTMT ER - TY - JOUR AU - Nagyné Naszályi, Lívia AU - Dhaene, Evert AU - Van Zele, Matthias AU - Mihály, Judith AU - Klébert, Szilvia AU - Varga, Zoltán AU - E Kövér, Katalin AU - De Buysser, Klaartje AU - Van Driessche, Isabel AU - Martins, José C. AU - Fehér, Krisztina TI - Silica@zirconia Core@shell Nanoparticles for Nucleic Acid Building Block Sorption JF - NANOMATERIALS J2 - NANOMATERIALS-BASEL VL - 11 PY - 2021 IS - 9 PG - 22 SN - 2079-4991 DO - 10.3390/nano11092166 UR - https://m2.mtmt.hu/api/publication/32164498 ID - 32164498 N1 - Funding Agency and Grant Number: European UnionEuropean Commission [703374]; FWO-VlaanderenFWO; Ghent UniversityGhent University [BOF2015/GOA/007]; Marie Curie Career Integration Grant [303917 PGN-INNATE]; Research Foundation-FlandersFWO [1525517N]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences [BO/004333/18/7]; New National Excellence Program of Debrecen University [uNKP-20-4-DE-165 Bolyai+]; National Research, Development and Innovation Office of HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [NKFI/OTKA NN 128368] Funding text: This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 703374. E.D. acknowledges FWO-Vlaanderen for a fellowship (FWO-SB fellowship). I.V.D. acknowledges Ghent University (project BOF2015/GOA/007). K.F. acknowledges the support of the Marie Curie Career Integration Grant (303917 PGN-INNATE) and the Research Grant from the Research Foundation-Flanders (1525517N), the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (uNKP-20-4-DE-165 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368). AB - The development of delivery systems for the immobilization of nucleic acid cargo molecules is of prime importance due to the need for safe administration of DNA or RNA type of antigens and adjuvants in vaccines. Nanoparticles (NP) in the size range of 20–200 nm have attractive properties as vaccine carriers because they achieve passive targeting of immune cells and can enhance the immune response of a weakly immunogenic antigen via their size. We prepared high capacity 50 nm diameter silica@zirconia NPs with monoclinic/cubic zirconia shell by a green, cheap and up-scalable sol–gel method. We studied the behavior of the particles upon water dialysis and found that the ageing of the zirconia shell is a major determinant of the colloidal stability after transfer into the water due to physisorption of the zirconia starting material on the surface. We determined the optimum conditions for adsorption of DNA building blocks, deoxynucleoside monophosphates (dNMP), the colloidal stability of the resulting NPs and its time dependence. The ligand adsorption was favored by acidic pH, while colloidal stability required neutral-alkaline pH; thus, the optimal pH for the preparation of nucleic acid-modified particles is between 7.0–7.5. The developed silica@zirconia NPs bind as high as 207 mg dNMPs on 1 g of nanocarrier at neutral-physiological pH while maintaining good colloidal stability. We studied the influence of biological buffers and found that while phosphate buffers decrease the loading dramatically, other commonly used buffers, such as HEPES, are compatible with the nanoplatform. We propose the prepared silica@zirconia NPs as promising carriers for nucleic acid-type drug cargos. LA - English DB - MTMT ER - TY - JOUR AU - Manček-Keber, Mateja AU - Ribić, Rosana AU - Chain, Fernando AU - Sinnaeve, Davy AU - Martins, José C. AU - Jerala, Roman AU - Tomić, Srđanka AU - Fehér, Krisztina TI - Adamantane Containing Peptidoglycan Fragments Enhance RANTES and IL-6 Production in Lipopolysaccharide-Induced Macrophages JF - MOLECULES J2 - MOLECULES VL - 25 PY - 2020 IS - 16 PG - 10 SN - 1420-3049 DO - 10.3390/molecules25163707 UR - https://m2.mtmt.hu/api/publication/31606798 ID - 31606798 N1 - Funding Agency and Grant Number: Slovenian Research AgencySlovenian Research Agency - Slovenia [P4-0176, J3-8196, J3-9257]; Croatian Science Foundation [IP-2014-09-7899]; Erasmus Mundus Peace fellowship; Marie Curie Career Integration GrantEuropean Union (EU) [303917 PGN-INNATE]; Research Foundation-FlandersFWO [1508414N, 1525517N]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences [BO/004333/18/7]; New National Excellence Program of Debrecen University [UNKP-19-4 Bolyai+]; National Research, Development and Innovation Office of Hungary [NKFI/OTKA NN 128368] Funding text: M.M.-K. and R.J. acknowledge the support from Slovenian Research Agency (program P4-0176, project no. J3-8196 and J3-9257 to MMK). R.R. and S.T. wish to thank the Croatian Science Foundation for support (project IP-2014-09-7899). F.C. thanks the Erasmus Mundus Peace fellowship. K.F. acknowledges the support of the Marie Curie Career Integration Grant (303917 PGN-INNATE) and the Research Grant from the Research Foundation-Flanders (1508414N and 1525517N), the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (UNKP-19-4 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368). Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, P.O. Box 660, Ljubljana, SI-1001, Slovenia Centre of Excelence EN-FIST, Ljubljana, SI-1000, Slovenia University Center Varaždin, University North, Jurja Križanića 31b, Varaždin, HR-42 000, Croatia Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, Ghent, 9000, Belgium Univ. Lille, Inserm, Institut Pasteur de Lille, CHU Lille, U1167—Labex DISTALZ—RID-AGE—Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, F-59000, France CNRS, ERL9002—Integrative Structural Biology, Lille, F-59000, France Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, Zagreb, HR-10 000, Croatia Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, Heidelberg, 69118, Germany Molecular Recognition and Interaction Research Group, Hungarian Academy of Sciences, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary Export Date: 2 February 2021 CODEN: MOLEF Correspondence Address: Fehér, K.; Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, Germany; email: feher.krisztina@science.unideb.hu Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, J3-9257, P4-0176, J3-8196 Funding details: Marie Curie, 303917 PGN-INNATE Funding details: National Research, Development and Innovation Office, NKFI/OTKA NN 128368 Funding details: 1525517N, 1508414N Funding details: Magyar Tudományos Akadémia, MTA, BO/004333/18/7 Funding details: Hrvatska Zaklada za Znanost, HRZZ, IP-2014-09-7899 Funding text 1: Funding: M.M.-K. and R.J. acknowledge the support from Slovenian Research Agency (program P4-0176, project no. J3-8196 and J3-9257 to MMK). R.R. and S.T. wish to thank the Croatian Science Foundation for support (project IP-2014-09-7899). F.C. thanks the Erasmus Mundus Peace fellowship. K.F. acknowledges the support of the Marie Curie Career Integration Grant (303917 PGN-INNATE) and the Research Grant from the Research Foundation-Flanders (1508414N and 1525517N), the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (ÚNKP-19-4 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368). AB - We report the enhancement of the lipopolysaccharide-induced immune response by adamantane containing peptidoglycan fragments in vitro. The immune stimulation was detected by Il-6 (interleukine 6) and RANTES (regulated on activation, normal T cell expressed and secreted) chemokine expression using cell assays on immortalized mouse bone-marrow derived macrophages. The most active compound was a α-D-mannosyl derivative of an adamantylated tripeptide with L-chirality at the adamantyl group attachment, whereby the mannose moiety assumed to target mannose receptors expressed on macrophage cell surfaces. The immune co-stimulatory effect was also influenced by the configuration of the adamantyl center, revealing the importance of specific molecular recognition event taking place with its receptor. The immunostimulating activities of these compounds were further enhanced upon their incorporation into lipid bilayers, which is likely related to the presence of the adamantyl group that helps anchor the peptidoglycan fragment into lipid nanoparticles. We concluded that the proposed adamantane containing peptidoglycan fragments act as co-stimulatory agents and are also suitable for the preparation of lipid nanoparticle-based delivery of peptidoglycan fragments. LA - English DB - MTMT ER - TY - JOUR AU - Ribic, Rosana AU - Mancek-Keber, Mateja AU - Chain, Fernando AU - Sinnaeve, Davy AU - Martins, Jose C. AU - Jerala, Roman AU - Tomic, Srdanka AU - Fehér, Krisztina TI - Targeted Delivery of Adamantylated Peptidoglycan Immunomodulators in Lipid Nanocarriers: NMR Shows That Cargo Fragments Are Available on the Surface JF - JOURNAL OF PHYSICAL CHEMISTRY B J2 - J PHYS CHEM B VL - 124 PY - 2020 IS - 20 SP - 4132 EP - 4145 PG - 14 SN - 1520-6106 DO - 10.1021/acs.jpcb.0c00029 UR - https://m2.mtmt.hu/api/publication/31495393 ID - 31495393 N1 - Funding Agency and Grant Number: Croatian Science Foundation [IP-2014-09-7899]; Slovenian Research AgencySlovenian Research Agency - Slovenia [P4-0176]; Erasmus Mundus Peace fellowship; Research Foundation-Flanders (FWO-Vlaanderen)FWO [1.5.133.13N]; Marie Curie Career Integration GrantEuropean Union (EU) [303917 PGN-INNATE]; Research Foundation-FlandersFWO [1508414N, 1525517N]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences [BO/004333/18/7]; New National Excellence Program of Debrecen University [UNKP-19-4]; National Research, Development and Innovation Office of Hungary [NKFI/OTKA NN 128368]; FFEU-ZWAP initiative of the Flemish Government Funding text: R.R. and S.T. wish to thank the Croatian Science Foundation for support (project IP-2014-09-7899). M.M.-K. and R.J. acknowledge support from the Slovenian Research Agency (program no. P4-0176). F.C. is thankful for the Erasmus Mundus Peace fellowship. D.S. thanks the Research Foundation-Flanders (FWO-Vlaanderen) for a postdoctoral research fellowship and a research grant (1.5.133.13N). K.F. acknowledges the support of the Marie Curie Career Integration Grant (303917 PGN-INNATE) and the Research Grant from the Research Foundation-Flanders (1508414N and 1525517N), Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (UNKP-19-4 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368). The authors thank Dr. Ruz.a Frkanec, Prof. Laszlo Szilagyi, and Dr. Niels Geudens for stimulating discussions. The 700 MHz equipment in this work was funded by the FFEU-ZWAP initiative of the Flemish Government. University Center Varaždin, University North, Jurja Križanicá 31b, Varaždin, HR-42 000, Croatia Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, P.O. Box 660, Ljubljana, SI-1001, Slovenia Department of Organic and Macromolecular Chemistry, Ghent University, Campus Sterre S4, Krijgslaan 281, Ghent, 9000, Belgium Univ. Lille, Inserm, Institut Pasteur de Lille, Chu Lille, U1167-Labex DISTALZ-RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, F-59000, France Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, Zagreb, HR-10 000, Croatia Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, Heidelberg, 69118, Germany Molecular Recognition and Interaction Research Group, Hungarian Academy of Sciences, Egyetem tér 1, Debrecen, H-4032, Hungary Cnrs, ERL9002-Integrative Structural Biology, Lille, F-59000, France Cited By :1 Export Date: 2 February 2021 CODEN: JPCBF Correspondence Address: Fehér, K.; Department of Organic and Macromolecular Chemistry, Campus Sterre S4, Krijgslaan 281, Belgium; email: feher.krisztina@science.unideb.hu Correspondence Address: Fehér, K.; Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, Germany; email: feher.krisztina@science.unideb.hu Correspondence Address: Fehér, K.; Molecular Recognition and Interaction Research Group, Egyetem tér 1, Hungary; email: feher.krisztina@science.unideb.hu Funding details: 1.5.133.13N Funding details: Vlaamse regering Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, P4-0176 Funding details: Marie Curie, 303917 PGN-INNATE, 1525517N, 1508414N Funding details: National Research, Development and Innovation Office, NKFI/OTKA NN 128368 Funding details: Magyar Tudományos Akadémia, MTA, BO/004333/18/7 Funding details: Hrvatska Zaklada za Znanost, HRZZ, IP-2014-09-7899 Funding text 1: R.R. and S.T. wish to thank the Croatian Science Foundation for support (project IP-2014-09-7899). M.M.-K. and R.J. acknowledge support from the Slovenian Research Agency (program no. P4-0176). F.C. is thankful for the Erasmus Mundus Peace fellowship. D.S. thanks the Research Foundation-Flanders (FWO-Vlaanderen) for a postdoctoral research fellowship and a research grant (1.5.133.13N). K.F. acknowledges the support of the Marie Curie Career Integration Grant (303917 PGN-INNATE) and the Research Grant from the Research Foundation-Flanders (1508414N and 1525517N), János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (ÚNKP-19-4 Bolyai+). This research was supported by the National Research, Development and Innovation Office of Hungary (grant NKFI/OTKA NN 128368). The authors thank Dr. Ruža Frkanec, Prof. László Szilágyi, and Dr. Niels Geudens for stimulating discussions. The 700 MHz equipment in this work was funded by the FFEU-ZWAP initiative of the Flemish Government. AB - We present an in-depth investigation of the membrane interactions of peptidoglycan (PGN)-based immune adjuvants designed for lipid-based delivery systems using NMR spectroscopy. The derivatives contain a cargo peptidoglycan (PGN) dipeptide fragment and an adamantyl group, which serves as an anchor to the lipid bilayer. Furthermore, derivatives with a mannose group that can actively target cell surface receptors on immune cells are also studied. We showed that the targeting mannose group and the cargo PGN fragment are both available on the lipid bilayer surface, thereby enabling interactions with cognate receptors. We found that the nonmannosylated compounds are incorporated stronger into the lipid assemblies than the mannosylated ones, but the latter compounds penetrate deeper in the bilayer. This might be explained by stronger electrostatic interactions available for zwitterionic nonmannosylated derivatives as opposed to the compounds in which the charged N-terminus is capped by mannose groups. The higher incorporation efficiency of the nonmannosylated compounds correlated with a larger relative enhancement in immune stimulation activities upon lipid incorporation compared to that of the derivatives with the mannose group. The chirality of the adamantyl group also influenced the incorporation efficiency, which in turn correlated with membrane-associated conformations that affect possible intermolecular interactions with lipid molecules. These findings will help in improving the development of PGN-based immune adjuvants suitable for delivery in lipid nanoparticles. LA - English DB - MTMT ER -