TY - JOUR AU - Dibello, Estefanía AU - Oddone, Natalia AU - Franco, Jaime AU - Tóthné Illyés, Tünde Zita AU - Medeiros, Andrea AU - Kiss, Attila AU - Hőgye, Fanni AU - E Kövér, Katalin AU - Szilágyi, László AU - Comini, Marcelo A. TI - Selenosugars targeting the infective stage of Trypanosoma brucei with high selectivity JF - INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE J2 - INT J PARASITOL-DRUG VL - 24 PY - 2024 PG - 6 SN - 2211-3207 DO - 10.1016/j.ijpddr.2024.100529 UR - https://m2.mtmt.hu/api/publication/34743720 ID - 34743720 AB - Earlier evidences showed that diglycosyl diselenides are active against the infective stage of African trypanosomes (top hits IC50 0.5 and 1.5 μM) but poorly selective (selectivity index <10). Here we extended the study to 33 new seleno-glycoconjugates with the aim to improve potency and selectivity. Three selenoglycosides and three glycosyl selenenylsulfides displayed IC50 against bloodstream Trypanosoma brucei in the sub-μM range (IC50 0.35–0.77 μM) and four of them showed an improved selectivity (selectivity index >38-folds vs. murine and human macrohages). For the glycosyl selenylsulfides, the anti-trypanosomal activity was not significantly influenced by the nature of the moiety attached to the sulfur atom. Except for a quinoline-, and to a minor extent a nitro-derivative, the most selective hits induced a rapid (within 60 min) and marked perturbation of the LMWTredox homeostasis. The formation of selenenylsulfide glycoconjugates with free thiols has been identified as a potential mechanism involved in this process. LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Balázs István AU - Bahar, Bazeli AU - Annelies, Janssens AU - Lisztes, Erika AU - Racskó, Márk AU - Kelemen, Balázs AU - Herczeg, Mihály AU - Nagy, Tamás Milán AU - E Kövér, Katalin AU - Argha, Mitra AU - Attila, Borics AU - Bíró, Tamás AU - Thomas, Voets TI - Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants JF - ELIFE J2 - ELIFE PY - 2024 SN - 2050-084X UR - https://m2.mtmt.hu/api/publication/34722559 ID - 34722559 N1 - preprint DOI-ja: 10.1101/2024.02.01.578392 LA - English DB - MTMT ER - TY - JOUR AU - Kónya, Zoltán AU - Tamás, István AU - Bécsi, Bálint AU - Lontay, Beáta AU - Hadháziné Raics, Mária AU - Timári, István AU - E Kövér, Katalin AU - Erdődi, Ferenc TI - Phosphorylated Peptide Derived from the Myosin Phosphatase Target Subunit Is a Novel Inhibitor of Protein Phosphatase-1 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 5 PG - 17 SN - 1661-6596 DO - 10.3390/ijms24054789 UR - https://m2.mtmt.hu/api/publication/33699950 ID - 33699950 AB - Identification of specific protein phosphatase-1 (PP1) inhibitors is of special importance regarding the study of its cellular functions and may have therapeutic values in diseases coupled to signaling processes. In this study, we prove that a phosphorylated peptide of the inhibitory region of myosin phosphatase (MP) target subunit (MYPT1), R690QSRRS(pT696)QGVTL701 (P-Thr696-MYPT1690−701), interacts with and inhibits the PP1 catalytic subunit (PP1c, IC50 = 3.84 µM) and the MP holoenzyme (Flag-MYPT1-PP1c, IC50 = 3.84 µM). Saturation transfer difference NMR measurements established binding of hydrophobic and basic regions of P-Thr696-MYPT1690−701 to PP1c, suggesting interactions with the hydrophobic and acidic substrate binding grooves. P-Thr696-MYPT1690−701 was dephosphorylated by PP1c slowly (t1/2 = 81.6–87.9 min), which was further impeded (t1/2 = 103 min) in the presence of the phosphorylated 20 kDa myosin light chain (P-MLC20). In contrast, P-Thr696-MYPT1690−701 (10–500 µM) slowed down the dephosphorylation of P-MLC20 (t1/2 = 1.69 min) significantly (t1/2 = 2.49–10.06 min). These data are compatible with an unfair competition mechanism between the inhibitory phosphopeptide and the phosphosubstrate. Docking simulations of the PP1c-P-MYPT1690−701 complexes with phosphothreonine (PP1c-P-Thr696-MYPT1690−701) or phosphoserine (PP1c-P-Ser696-MYPT1690−701) suggested their distinct poses on the surface of PP1c. In addition, the arrangements and distances of the surrounding coordinating residues of PP1c around the phosphothreonine or phosphoserine at the active site were distinct, which may account for their different hydrolysis rate. It is presumed that P-Thr696-MYPT1690−701 binds tightly at the active center but the phosphoester hydrolysis is less preferable compared to P-Ser696-MYPT1690−701 or phosphoserine substrates. Moreover, the inhibitory phosphopeptide may serve as a template to synthesize cell permeable PP1-specific peptide inhibitors. 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 IS - 1 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 - Király, Sándor Balázs AU - Tóth, László AU - Kovács, Tibor AU - Bényei, Attila Csaba AU - Lisztes, Erika AU - Tóth, Balázs István AU - Bíró, Tamás AU - Kiss, Attila AU - E Kövér, Katalin AU - Mándi, Attila AU - Kurtán, Tibor TI - Multifaceted Domino Knoevenagel‐Cyclization Reactions; Four Movements for 2H‐Chromenes and Chromans JF - ADVANCED SYNTHESIS & CATALYSIS J2 - ADV SYNTH CATAL VL - 365 PY - 2023 IS - 19 SP - 3301 EP - 3319 PG - 19 SN - 1615-4150 DO - 10.1002/adsc.202300083 UR - https://m2.mtmt.hu/api/publication/33683947 ID - 33683947 AB - Domino Knoevenagel-cyclization reactions of 2H-chromene and chroman derivatives containing o-formylaryl amine or ether side-chain was carried out to produce four series of chiral condensed heterocycles representing four novel skeletons and exhibiting antiproliferative activity. The cyclization step occurred with four different mechanisms: a concerted intramolecular hetero Diels-Alder reaction (IMHDA), a stepwise polar [2+2] cycloaddition, a [1,5]-hydride shift-6-endo cyclization or a multi-step nitro hetero Diels-Alder-ring-opening-Cadogan-type cyclization sequence. The latter reaction provided a new route to hydroxyindoles by an inverse Cadogan-type cyclization, in which the nitro group is deoxygenated by a nitro IMHDA-ring-opening sequence. The cyclization mechanisms and their stereoselectivity were studied by DFT calculations, based on which we proposed a mechanism for the multi-step cyclization to hydroxyindoles and explained the observed diastereoselectivity. LA - English DB - MTMT ER - TY - JOUR AU - Czajlik, András AU - Batta, Ágnes AU - Kerner, Kinga AU - Fizil, Ádám AU - Hajdu, Dorottya Zsuzsanna AU - Hadháziné Raics, Mária AU - E Kövér, Katalin AU - Batta, Gyula TI - DMSO-Induced Unfolding of the Antifungal Disulfide Protein PAF and Its Inactive Variant: A Combined NMR and DSC Study JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 2 PG - 13 SN - 1661-6596 DO - 10.3390/ijms24021208 UR - https://m2.mtmt.hu/api/publication/33550734 ID - 33550734 N1 - Department of Organic Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary Department of Biochemistry, Institute of Biochemistry and Molecular Biology, Semmelweis University, Tűzoltó utca 37-47, Budapest, H-1094, Hungary Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary Department of Inorganic and Analytical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary MTA-DE Molecular Recognition and Interaction Research Group, Department of Inorganic and Analytical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem tér 1, Debrecen, H-4032, Hungary Export Date: 18 September 2023 Correspondence Address: Batta, G.; Department of Organic Chemistry, Egyetem tér 1, Hungary; email: batta@unideb.hu AB - PAF and related antifungal proteins are promising antimicrobial agents. They have highly stable folds around room temperature due to the presence of 3–4 disulfide bonds. However, unfolded states persist and contribute to the thermal equilibrium in aqueous solution, and low-populated states might influence their biological impact. To explore such equilibria during dimethyl sulfoxide (DMSO)-induced chemical unfolding, we studied PAF and its inactive variant PAFD19S using nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). According to the NMR monitoring at 310 K, the folded structures disappear above 80 v/v% DMSO concentration, while the unfolding is completely reversible. Evaluation of a few resolved peaks from viscosity-compensated 15N-1H HSQC spectra of PAF yielded ∆G = 23 ± 7 kJ/M as the average value for NMR unfolding enthalpy. The NMR-based structures of PAF and the mutant in 50 v/v% DMSO/H2O mixtures were more similar in the mixed solvents then they were in water. The 15N NMR relaxation dynamics in the same mixtures verified the rigid backbones of the NMR-visible fractions of the proteins; still, enhanced dynamics around the termini and some loops were observed. DSC monitoring of the Tm melting point showed parabolic dependence on the DMSO molar fraction and suggested that PAF is more stable than the inactive PAFD19S. The DSC experiments were irreversible due to the applied broad temperature range, but still suggestive of the endothermic unfolding of PAF. LA - English DB - MTMT ER - TY - JOUR AU - Csávás, Magdolna AU - Kalmár, László AU - Szoke, Petronella AU - Farkas, László Bence AU - Bécsi, Bálint AU - Kónya, Zoltán AU - Kerékgyártó, János AU - Borbás, Anikó AU - Erdődi, Ferenc AU - E Kövér, Katalin TI - A Fucosylated Lactose-Presenting Tetravalent Glycocluster Acting as a Mutual Ligand of Pseudomonas aeruginosa Lectins A (PA-IL) and B (PA-IIL)-Synthesis and Interaction Studies JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 24 PG - 14 SN - 1661-6596 DO - 10.3390/ijms232416194 UR - https://m2.mtmt.hu/api/publication/33554482 ID - 33554482 N1 - Funding: The synthetic work was supported by the National Research and Development and Innovation Office of Hungary (K119509 to M. Cs., K129104 to F.E. and NN128368 K.E.K.) and the EU and co-financed by the European Regional Development Fund under the projects GINOP-2.3.2-15- 2016-00008, GINOP-2.3.3-15-2016-00004 and GINOP-2.3.4-15-2020-00008. AB - The Gram-negative bacterium Pseudomonas aeruginosa is an important opportunistic human pathogen associated with cystic fibrosis. P. aeruginosa produces two soluble lectins, the d-galactose-specific lectin PA-IL (LecA) and the l-fucose-specific lectin PA-IIL (LecB), among other virulence factors. These lectins play an important role in the adhesion to host cells and biofilm formation. Moreover, PA-IL is cytotoxic to respiratory cells in the primary culture. Therefore, these lectins are promising therapeutic targets. Specifically, carbohydrate-based compounds could inhibit their activity. In the present work, a 3-O-fucosyl lactose-containing tetravalent glycocluster was synthesized and utilized as a mutual ligand of galactophilic and fucophilic lectins. Pentaerythritol equipped with azido ethylene glycol-linkers was chosen as a multivalent scaffold and the glycocluster was constructed by coupling the scaffold with propargyl 3-O-fucosyl lactoside using an azide-alkyne 1,3-dipolar cycloaddition reaction. The interactions between the glycocluster and PA-IL or PA-IIL were investigated by isothermal titration microcalorimetry and saturation transfer difference NMR spectroscopy. These results may assist in the development of efficient anti-adhesion therapy for the treatment of a P. aeruginosa infection. LA - English DB - MTMT ER - TY - JOUR AU - Herczeg, Mihály AU - Demeter, Fruzsina AU - Lisztes, Erika AU - Racskó, Márk AU - Tóth, Balázs István AU - Timári, István AU - Bereczky, Zsuzsanna AU - E Kövér, Katalin AU - Borbás, Anikó TI - Synthesis of a Heparinoid Pentasaccharide Containing L-Guluronic Acid Instead of L-Iduronic Acid with Preserved Anticoagulant Activity JF - JOURNAL OF ORGANIC CHEMISTRY J2 - J ORG CHEM VL - 87 PY - 2022 IS - 23 SP - 15830 EP - 15836 PG - 7 SN - 0022-3263 DO - 10.1021/acs.joc.2c01928 UR - https://m2.mtmt.hu/api/publication/33332835 ID - 33332835 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [K 132870, K 139293, NN 128368, FK 137924, PD 134791, PD 135034]; Premium Postdoctoral Program of HAS [PPD 461038]; EU; European Regional Development Fund [GINOP-2.3.4-15-2020-00008, GINOP-2.3.3-15-2016-00004]; Janos Bolyai Scholarship of the Hungarian Academy of Science; Debrecen Venture Catapult [EFOP-3.6.1-16-2016-0022]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00372/20/7]; New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund [UNKP-22-5-DE-424] Funding text: The research was supported by the National Research, Development and Innovation Office of Hungary (K 132870, A.B.; K 139293, Z.B.; NN 128368, K.E.K.; FK 137924, M.H.; PD 134791, E.L., and PD 135034, I.T.), Premium Postdoctoral Program of HAS (PPD 461038, M.H.), and the EU and co-financed by the European Regional Development Fund under the project GINOP-2.3.4-15-2020-00008 and GINOP-2.3.3-15-2016-00004. B.I.T. was supported by the Janos Bolyai Scholarship of the Hungarian Academy of Science, and M.R. was supported by EFOP-3.6.1-16-2016-0022 "Debrecen Venture Catapult." I.T. acknowledges the support of the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the UNKP-22-5-DE-424 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund . The authors would like to thank Marta Bodza and EEva Molnar for their technical assistance. AB - L-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that L-iduronic acid can be replaced by an easier-to-produce L-sugar while maintaining its essential biological activity. From the inexpensive D-mannose, through a highly functionalized phenylthio mannoside, the L-gulose donor was prepared by C-5 epimerization in 10 steps with excellent yield. This unit was incorporated into the pentasaccharide by alpha-selective glycosylation and oxidized to L-guluronic acid. The complete synthesis required only 36 steps, with 21 steps for the longest linear route. The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of L-iduronic acid. LA - English DB - MTMT ER - TY - JOUR AU - Timári, István AU - Bagi, Péter AU - Keglevich, György AU - E Kövér, Katalin TI - Ultrahigh-Resolution Homo- and Heterodecoupled 1H and TOCSY NMR Experiments JF - ACS OMEGA J2 - ACS OMEGA VL - 7 PY - 2022 IS - 47 SP - 43283 EP - 43289 PG - 7 SN - 2470-1343 DO - 10.1021/acsomega.2c06102 UR - https://m2.mtmt.hu/api/publication/33258379 ID - 33258379 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [PD 135034, NN 128368, K 134318]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00372/20/7]; New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund [UNKP-22-5-DE-424] Funding text: This research was supported by the National Research, Development and Innovation Office of Hungary (grant numbers: PD 135034 (to I.T.), NN 128368 (to K.E.K.), and K 134318 (to G.K.)). The I.T. research was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the UNKP-22-5-DE-424 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. AB - The original homonuclear decoupled (pure shift) experiments provide ultrahigh-resolution 1H spectra of compounds containing NMR-active heteronuclei of low natural isotopic abundance (e.g., 13C or 15N). In contrast, molecules containing highly abundant heteronuclei (like 31P or 19F) give doublets or a multiple of doublets in their homonuclear decoupled spectra, depending on the number of heteronuclear coupling partners and the magnitude of the respective coupling constants. In these cases, the complex and frequently overlapping signals may hamper the unambiguous assignment of resonances. Here, we present new heteronuclear decoupled (HD) PSYCHE 1H and TOCSY experiments, which result in simplified spectra with significantly increased resolution, allowing the reliable assessment of individual resonances. The utility of the experiments has been demonstrated on a challenging stereoisomeric mixture of a platinum–phosphine complex, where ultrahigh resolution of the obtained HD PSYCHE spectra made the structure elucidation of the chiral products feasible. HD PSYCHE methods can be potentially applied to other important 31P- or 19F-containing compounds in medicinal chemistry and metabolomics. LA - English DB - MTMT ER - TY - JOUR AU - Farkas, László Bence AU - Timári, István AU - E Kövér, Katalin AU - Sørensen, Ole W. TI - Four-in-one: HSQC, HSQC-TOCSY (or H2BC), TOCSY, and enhanced HMBC spectra integrated into a single NO Relaxation Delay (NORD) NMR experiment JF - JOURNAL OF MAGNETIC RESONANCE J2 - J MAGN RESON VL - 343 PY - 2022 PG - 7 SN - 1090-7807 DO - 10.1016/j.jmr.2022.107297 UR - https://m2.mtmt.hu/api/publication/33090799 ID - 33090799 N1 - This research was supported by the National Research, Development and Innovation Office of Hungary (grants NKFI/OTKA NN 128368 and PD 135034) 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). I.T. acknowledges the support of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the ÚNKP-22-5-DE-424 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. AB - The NMR pulse sequence design strategy of NORD (NO Relaxation Delay) is extended to design of two new three-module experiments, NORD {HMBC}-{HSQC-TOCSY}-{TOCSY} and NORD {HMBC}-{2BOB}-{TOCSY}, each delivering four spectra - HMBC, HSQC, TOCSY, and either HSQC-TOCSY or H2BC. Compared to individual recording of these spectra particularly the sensitivity of the least sensitive mod-ule, HMBC, is enhanced by designing the homonuclear TOCSY module to allow buildup of magnetization pertinent to HMBC during its execution. Effectively, the sensitivity of the heteronuclear modules is boosted at the expense of the inherently much higher TOCSY sensitivity, thus resulting in a significant saving in spectrometer time. LA - English DB - MTMT ER -