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 - 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 - Fenteany, Gabriel AU - Sharma, Gaurav AU - Gaur, Paras AU - Borics, Attila AU - Wéber, Edit AU - Kiss, Ernő AU - Haracska, Lajos TI - A series of xanthenes inhibiting Rad6 function and Rad6–Rad18 interaction in the PCNA ubiquitination cascade JF - ISCIENCE J2 - ISCIENCE VL - 25 PY - 2022 IS - 4 PG - 23 SN - 2589-0042 DO - 10.1016/j.isci.2022.104053 UR - https://m2.mtmt.hu/api/publication/32746161 ID - 32746161 N1 - Funding Agency and Grant Number: E '.1-15-2017-00072; National Research, Development and Innovation OfficeNational Research, Development & Innovation Office (NRDIO) - Hungary [GINOP-2.3.2-15-2016-00024, GINOP-2.2.1-15-2017-00072]; European UnionEuropean Commission [739593] Funding text: We wish to acknowledge Tama ' sMartinek for sharing his expertise, as well as Katalin Kovacs, Katalin Konta ' r, and E ' va Hunyadi-Gulyas for their technical assistance and Gabriella Tick for proofreading the manuscript. We thank the US National Cancer Institute's Developmental Therapeutics Program for providing chemical libraries and individual compounds. This work was supported by the National Research, Development and Innovation Office (GINOP-2.3.2-15-2016-00024 and GINOP-2.2.1-15-2017-00072). This project has also received funding from the European Union's Horizon 2020 Research And Innovation Program under grant agreement No. 739593. AB - Ubiquitination of proliferating cell nuclear antigen (PCNA) triggers pathways of DNA damage tolerance, including mutagenic translesion DNA synthesis, and comprises a cascade of reactions involving the E1 ubiquitin-activating enzyme Uba1, the E2 ubiquitin-conjugating enzyme Rad6, and the E3 ubiquitin ligase Rad18. We report here the discovery of a series of xanthenes that inhibit PCNA ubiquitination, Rad6-ubiquitin thioester formation, and the Rad6-Rad18 interaction. Structure-activity relationship experiments across multiple assays reveal chemical and structural features important for different activities along the pathway to PCNA ubiquitination. The compounds that inhibit these processes are all a subset of the xanthen-3-ones we tested. These small molecules thus represent first-in-class probes of Rad6 function and the association of Rad6 and Rad18, the latter being a new inhibitory activity discovered for a small molecule, in the PCNA ubiquitination cascade and potential therapeutic agents to contain cancer progression. LA - English DB - MTMT ER - TY - JOUR AU - Tököli, Attila AU - Mag, Beáta Zsófia AU - Bartus, Éva AU - Wéber, Edit AU - Szakonyi, Gerda AU - Simon, Márton AU - Czibula, Ágnes AU - Monostori, Éva AU - Nyitray, László AU - Martinek, Tamás TI - Proteomimetic surface fragments distinguish targets by function JF - CHEMICAL SCIENCE J2 - CHEM SCI VL - 11 PY - 2020 IS - 38 SP - 10390 EP - 10398 PG - 9 SN - 2041-6520 DO - 10.1039/d0sc03525d UR - https://m2.mtmt.hu/api/publication/31598466 ID - 31598466 N1 - Department of Medical Chemistry, University of Szeged, Dóm tér 8, Szeged, H6720, Hungary MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Dóm tér 8, Szeged, H6720, Hungary Institute of Pharmaceutical Analysis, University of Szeged, Somogyi u. 4., Szeged, H6720, Hungary Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, Budapest, H1077, Hungary Lymphocyte Signal Transduction Laboratory, Institute of Genetics, Biological Research Centre, Temesvári krt. 62, H6726 Szeged, Hungary Cited By :3 Export Date: 8 May 2024 CODEN: CSHCC Correspondence Address: Nyitray, L.; Department of Biochemistry, Pázmány Péter sétány 1/C, Hungary; email: nyitray@elte.hu LA - English DB - MTMT ER - TY - JOUR AU - Fenteany, Gabriel AU - Gaur, Paras AU - Hegedűs, Lili AU - Dudás, Kata AU - Kiss, Ernő AU - Wéber, Edit AU - Hackler, László AU - Martinek, Tamás AU - Puskás, László AU - Haracska, Lajos TI - Multilevel structure–activity profiling reveals multiple green tea compound families that each modulate ubiquitin-activating enzyme and ubiquitination by a distinct mechanism JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 9 PY - 2019 IS - 1 PG - 16 SN - 2045-2322 DO - 10.1038/s41598-019-48888-6 UR - https://m2.mtmt.hu/api/publication/30791081 ID - 30791081 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office [GINOP-2.3.2-15-2016-00020, GINOP-2.3.2-15-2016-00026]; European Union [739593] Funding text: We wish to thank Katalin Kovacs, Gaurav Sharma, Lajos Pinter, and Monika Morocz for technical assistance. This work was supported by the National Research, Development and Innovation Office (GINOP-2.3.2-15-2016-00020 and GINOP-2.3.2-15-2016-00026). This project has also received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 739593. HCEMM-BRC Mutagenesis and Carcinogenesis Research Group, Institute of Genetics, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, 6726, Hungary Department of Medical Chemistry, University of Szeged, Szeged, 6720, Hungary AstridBio Technologies Ltd., Szeged, 6726, Hungary Laboratory of Functional Genomics, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, 6726, Hungary Avicor Ltd., Szeged, 6726, Hungary Cited By :2 Export Date: 11 May 2021 Correspondence Address: Fenteany, G.; HCEMM-BRC Mutagenesis and Carcinogenesis Research Group, Hungary; email: fenteany.gabriel@brc.mta.hu Funding Agency and Grant Number: National Research, Development and Innovation OfficeNational Research, Development & Innovation Office (NRDIO) - Hungary [GINOP-2.3.2-15-2016-00020, GINOP-2.3.2-15-2016-00026]; European UnionEuropean Commission [739593] Funding text: We wish to thank Katalin Kovacs, Gaurav Sharma, Lajos Pinter, and Monika Morocz for technical assistance. This work was supported by the National Research, Development and Innovation Office (GINOP-2.3.2-15-2016-00020 and GINOP-2.3.2-15-2016-00026). This project has also received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 739593. LA - English DB - MTMT ER - TY - JOUR AU - Olajos, Gábor AU - Hetényi, Anasztázia AU - Wéber, Edit AU - Szögi, Titanilla AU - Fülöp, Lívia AU - Martinek, Tamás TI - Peripheral cyclic β-amino acids balance the stability and edge-protection of β-sandwiches JF - ORGANIC & BIOMOLECULAR CHEMISTRY J2 - ORG BIOMOL CHEM VL - 16 PY - 2018 IS - 30 SP - 5492 EP - 5499 PG - 8 SN - 1477-0520 DO - 10.1039/c8ob01322e UR - https://m2.mtmt.hu/api/publication/3399101 ID - 3399101 N1 - Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet program (LP-2011-009) and GINOP-2.3.3-15-2016-00010. E. W. thanks the Postdoctoral Fellowship Program 2014 of the Hungarian Academy of Sciences. AB - Engineering water-soluble stand-alone beta-sandwich mimetics is a current challenge because of the difficulties associated with tailoring long-range interactions. In this work, single cis-(1R,2S)-2-aminocyclohexanecarboxylic acid mutations were introduced into the edge strands of the eight-stranded beta-sandwich mimetic structures from the betabellin family. Temperature-dependent NMR and CD measurements, together with thermodynamic analyses, demonstrated that the modified peripheral strands exhibited an irregular and partially disordered structure but were able to exert sufficient shielding on the hydrophobic core to retain the predominantly beta-sandwich structure. Although the frustrated interactions decreased the free energy of unfolding, the temperature of the maximum stabilities increased to or remained at physiologically relevant temperatures. We found that the irregular peripheral strands were able to prevent edge-to-edge association and fibril formation in the aggregation-prone model. These findings establish a beta-sandwich stabilization and aggregation inhibition approach, which does not interfere with the pillars of the peptide bond or change the net charge of the peptide. LA - English DB - MTMT ER - TY - JOUR AU - Angyal, Anikó AU - Demjén, András AU - Wéber, Edit AU - Kovács, Anita Kármen AU - Wölfling, János AU - Puskás, László AU - Kanizsai, Iván TI - Lewis Acid-Catalyzed Diastereoselective Synthesis of Multisubstituted N-Acylaziridine-2-carboxamides from 2H-Azirines via Joullie-Ugi Three-Component Reaction JF - JOURNAL OF ORGANIC CHEMISTRY J2 - J ORG CHEM VL - 83 PY - 2018 IS - 7 SP - 3570 EP - 3581 PG - 12 SN - 0022-3263 DO - 10.1021/acs.joc.7b03189 UR - https://m2.mtmt.hu/api/publication/3389411 ID - 3389411 AB - A ZnCl2-catalyzed diastereoselective Joullie Ugi three-component reaction from 2H-azirines, isocyanides, and carboxylic acids was established. The protocol allows the preparation of highly and diversely functionalized N-acylaziridine-2-carboxamide derivatives in up to 82% isolated yields. Moreover, the applicability of N-acylaziridines is demonstrated through a variety of transformations. LA - English DB - MTMT ER - TY - JOUR AU - Háznagyné Radnai, Erzsébet AU - Fási, Laura AU - Wéber, Edit AU - Pinke, Gyula AU - Király, Botond Gergely AU - Sztojkov-Ivanov, Anita AU - Gáspár, Róbert AU - Hohmann, Judit TI - Anti-inflammatory Activity of Melampyrum barbatum and Isolation of Iridoid and Flavonoid Compounds JF - NATURAL PRODUCT COMMUNICATIONS J2 - NAT PROD COMMUN VL - 13 PY - 2018 IS - 3 SP - 235 EP - 236 PG - 2 SN - 1934-578X DO - 10.1177/1934578x1801300301 UR - https://m2.mtmt.hu/api/publication/3347203 ID - 3347203 AB - Melampyrum barbatum Waldst. & Kit. ex Willd. (Scrophulariaceae) has been used in traditional medicine for the treatment of rheumatic complaints and different skin diseases. In the course of our study the anti-inflammatory activity of the aerial parts of M barbatum was evaluated. A MeOH extract was prepared and consecutively partitioned with CHCl3, EtOAc and n-BuOH. The fractions were assayed in in vivo carrageenan-induced rat paw oedema model. The intraperitoneally administered n-BuOH phase exerted marked inhibitory effect (33.6 %, p < 0.01). Multistep chromatographic separation afforded mussaenoside and aucubine from n-BuOH fraction. Moreover, 8-epiloganin, loganic acid and mussaenoside were obtained from EtOAc fraction and apigenin, luteolin, benzoic acid and galactitol from CHCl3 fraction. These data validate the ethnomedicinal use of M barbatum for the treatment of inflammatory diseases and reveal that iridoids and flavonoids could be responsible for the anti-inflammatory effect of this species. LA - English DB - MTMT ER - TY - JOUR AU - Bartus, Éva AU - Hegedüs, Zsófia AU - Wéber, Edit AU - Csipak, Brigitta AU - Szakonyi, Gerda AU - Martinek, Tamás TI - De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach JF - CHEMISTRYOPEN J2 - CHEMISTRYOPEN VL - 6 PY - 2017 IS - 2 SP - 236 EP - 241 PG - 6 SN - 2191-1363 DO - 10.1002/open.201700012 UR - https://m2.mtmt.hu/api/publication/3213189 ID - 3213189 LA - English DB - MTMT ER - TY - JOUR AU - Hetényi, Anasztázia AU - Németh, Lukács AU - Wéber, Edit AU - Szakonyi, Gerda AU - Winter, Zoltán AU - Jósvay, Katalin AU - Bartus, Éva AU - Oláh, Zoltán AU - Martinek, Tamás TI - Competitive inhibition of TRPV1 – calmodulin interaction by vanilloids JF - FEBS LETTERS J2 - FEBS LETT VL - 590 PY - 2016 IS - 16 SP - 2768 EP - 2775 PG - 8 SN - 0014-5793 DO - 10.1002/1873-3468.12267 UR - https://m2.mtmt.hu/api/publication/3087152 ID - 3087152 N1 - Funding Agency and Grant Number: Hungarian Academy of Sciences; Lendulet Program [LP-2011-009]; MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]; Richter Gedeon Talentum Alapitvany; European Union; State of Hungary; European Social Fund [TAMOP-4.2.4.A/ 2-11/1-2012-0001]\n Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet Program (LP-2011-009), MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. (TP7-017), the Hungarian Research Foundation (OTKA K112442) and Financial support from Richter Gedeon Talentum Alapitvany (Ph.D. Scholarship to E.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/ 2-11/1-2012-0001 'National Excellence Program'.\n Funding Agency and Grant Number: Hungarian Academy of Sciences; Lendulet Program [LP-2011-009]; MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]; Richter Gedeon Talentum Alapitvany; European Union; State of Hungary; European Social Fund [TAMOP-4.2.4.A/ 2-11/1-2012-0001] Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet Program (LP-2011-009), MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. (TP7-017), the Hungarian Research Foundation (OTKA K112442) and Financial support from Richter Gedeon Talentum Alapitvany (Ph.D. Scholarship to E.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/ 2-11/1-2012-0001 'National Excellence Program'. AB - There is enormous interest toward vanilloid agonists of the pain receptor TRPV1 in analgesic therapy, but the mechanisms of their sensory neuron-blocking effects at high or repeated doses are still a matter of debate. Our results have demonstrated that capsaicin and resiniferatoxin form nanomolar complexes with calmodulin, and competitively inhibit TRPV1-calmodulin interaction. These interactions involve the protein recognition interface of calmodulin, which is responsible for all of the cell-regulatory calmodulin-protein interactions. These results draw attention to a previously unknown vanilloid target, which may contribute to the explanation of the paradoxical pain-modulating behavior of these important pharmacons. LA - English DB - MTMT ER -