TY - JOUR AU - Tánczos, Bence AU - Vass, Virág AU - Szabó, Erzsébet AU - Lovas, Miklós AU - Kattoub, Rasha Ghanem AU - Bakai-Bereczki, Ilona AU - Borbás, Anikó AU - Herczegh, Pál AU - Tósaki, Árpád TI - Effects of H2S-donor ascorbic acid derivative and ischemia/reperfusion-induced injury in isolated rat hearts JF - EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES J2 - EUR J PHARM SCI VL - 195 PY - 2024 IS - - SP - 106721 SN - 0928-0987 DO - 10.1016/j.ejps.2024.106721 UR - https://m2.mtmt.hu/api/publication/34572686 ID - 34572686 LA - English DB - MTMT ER - 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 - Bege, Miklós AU - Borbás, Anikó TI - The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19 JF - PHARMACEUTICS J2 - PHARMACEUTICS VL - 16 PY - 2024 IS - 2 PG - 17 SN - 1999-4923 DO - 10.3390/pharmaceutics16020217 UR - https://m2.mtmt.hu/api/publication/34557141 ID - 34557141 AB - The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed. LA - English DB - MTMT ER - TY - JOUR AU - Herczeg, Mihály AU - Demeter, Fruzsina AU - Nagy, Tibor AU - Rusznyák, Ágnes AU - Hodek, Jan AU - Sipos, Éva AU - Lekli, István AU - Fenyvesi, Ferenc AU - Weber, Jan AU - Kéki, Sándor AU - Borbás, Anikó TI - Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 1 SN - 1661-6596 DO - 10.3390/ijms25010677 UR - https://m2.mtmt.hu/api/publication/34502650 ID - 34502650 AB - Highly sulfated malto-oligomers, similar to heparin and heparan-sulfate, have good antiviral, antimetastatic, anti-inflammatory and cell growth inhibitory effects. Due to their broad biological activities and simple structure, sulfated malto-oligomer derivatives have a great therapeutic potential, therefore, the development of efficient synthesis methods for their production is of utmost importance. In this work, preparation of α-(1→4)-linked oligoglucosides containing a sulfonatomethyl moiety at position C-6 of each glucose unit was studied by different approaches. Malto-oligomeric sulfonic acid derivatives up to dodecasaccharides were prepared by polymerization using different protecting groups, and the composition of the product mixtures was analyzed by MALDI-MS methods and size-exclusion chromatography. Synthesis of lower oligomers was also accomplished by stepwise and block synthetic methods, and then the oligosaccharide products were persulfated. The antiviral, anti-inflammatory and cell growth inhibitory activity of the fully sulfated malto-oligosaccharide sulfonic acids were determined by in vitro tests. Four tested di- and trisaccharide sulfonic acids effectively inhibited the activation of the TNF-α-mediated inflammatory pathway without showing cytotoxicity. LA - English DB - MTMT ER - TY - JOUR AU - Lőrincz, Eszter Boglárka AU - Herczeg, Mihály AU - Houser, Josef AU - Rievajová, Martina AU - Kuki, Ákos AU - Malinovská, Lenka AU - Naesens, Lieve AU - Wimmerová, Michaela AU - Borbás, Anikó AU - Herczegh, Pál AU - Bakai-Bereczki, Ilona TI - Amphiphilic Sialic Acid Derivatives as Potential Dual-Specific Inhibitors of Influenza Hemagglutinin and Neuraminidase JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 24 PG - 23 SN - 1661-6596 DO - 10.3390/ijms242417268 UR - https://m2.mtmt.hu/api/publication/34427826 ID - 34427826 AB - In the shadow of SARS-CoV-2, influenza seems to be an innocent virus, although new zoonotic influenza viruses evolved by mutations may lead to severe pandemics. According to WHO, there is an urgent need for better antiviral drugs. Blocking viral hemagglutinin with multivalent N-acetylneuraminic acid derivatives is a promising approach to prevent influenza infection. Moreover, dual inhibition of both hemagglutinin and neuraminidase may result in a more powerful effect. Since both viral glycoproteins can bind to neuraminic acid, we have prepared three series of amphiphilic self-assembling 2-thio-neuraminic acid derivatives constituting aggregates in aqueous medium to take advantage of their multivalent effect. One of the series was prepared by the azide-alkyne click reaction, and the other two by the thio-click reaction to yield neuraminic acid derivatives containing lipophilic tails of different sizes and an enzymatically stable thioglycosidic bond. Two of the three bis-octyl derivatives produced proved to be active against influenza viruses, while all three octyl derivatives bound to hemagglutinin and neuraminidase from H1N1 and H3N2 influenza types. LA - English DB - MTMT ER - TY - JOUR AU - Lőrincz, Eszter Boglárka AU - Tóth, Gergely AU - Spolárics, Júlia AU - Herczeg, Mihály AU - Hodek, Jan AU - Zupkó, István AU - Minorics, Renáta AU - Ádám, Dorottya AU - Oláh, Attila AU - Zouboulis, Christos C. AU - Weber, Jan AU - Nagy, Lajos AU - Ostorházi, Eszter AU - Bácskay, Ildikó AU - Borbás, Anikó AU - Herczegh, Pál AU - Bakai-Bereczki, Ilona TI - Mannich-type modifications of (−)-cannabidiol and (−)-cannabigerol leading to new, bioactive derivatives JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 13 PY - 2023 IS - 1 PG - 20 SN - 2045-2322 DO - 10.1038/s41598-023-45565-7 UR - https://m2.mtmt.hu/api/publication/34316518 ID - 34316518 AB - (−)-Cannabidiol (CBD) and (−)-cannabigerol (CBG) are two major non-psychotropic phytocannabinoids that have many beneficial biological properties. However, due to their low water solubility and prominent first-pass metabolism, their oral bioavailability is moderate, which is unfavorable for medicinal use. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical and biological properties. In this study, Mannich-type reaction was used for the synthetic modification of CBD and CBG for the first time, and thus fifteen new cannabinoid derivatives containing one or two tertiary amino groups were prepared. Thereafter the antiviral, antiproliferative and antibacterial properties of the derivatives and their effects on certain skin cells were investigated. Some modified CBD derivatives showed remarkable antiviral activity against SARS-CoV-2 without cytotoxic effect, while synthetic modifications on CBG resulted in a significant increase in antiproliferative activity in some cases compared to the parent compound. LA - English DB - MTMT ER - TY - JOUR AU - Szőke, Kitti AU - Kajtár, Richárd AU - Gyöngyösi, Alexandra AU - Czompa, Attila AU - Fésüs, Adina AU - Lőrincz, Eszter Boglárka AU - Petróczi, Ferenc Dániel AU - Herczegh, Pál AU - Bak, István AU - Borbás, Anikó AU - Bakai-Bereczki, Ilona AU - Lekli, István TI - Pharmacological Evaluation of Newly Synthesized Cannabidiol Derivates on H9c2 Cells JF - ANTIOXIDANTS J2 - ANTIOXIDANTS-BASEL VL - 12 PY - 2023 IS - 9 PG - 15 SN - 2076-3921 DO - 10.3390/antiox12091714 UR - https://m2.mtmt.hu/api/publication/34125145 ID - 34125145 LA - English DB - MTMT ER - TY - JOUR AU - Bege, Miklós AU - Singh, Vigyasa AU - Sharma, Neha AU - Debreczeni, Nóra AU - Bakai-Bereczki, Ilona AU - Nam, Poo AU - Herczegh, Pál AU - Rathi, Brijesh AU - Singh, Shailja AU - Borbás, Anikó TI - In vitro and in vivo antiplasmodial evaluation of sugar-modified nucleoside analogues JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 13 PY - 2023 IS - 1 PG - 16 SN - 2045-2322 DO - 10.1038/s41598-023-39541-4 UR - https://m2.mtmt.hu/api/publication/34081319 ID - 34081319 AB - Drug-resistant Plasmodium falciparum ( Pf ) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing antimalarial therapies has complicated the problem, and the emergence of resistance to artemisinin derivatives is even more concerning. It is increasingly difficult to cure malaria patients due to the limited availability of effective antimalarial drugs, resulting in an urgent need for more efficacious and affordable treatments to eradicate this disease. Herein, new nucleoside analogues including morpholino-nucleoside hybrids and thio-substituted nucleoside derivatives were prepared and evaluated for in vitro and in vivo antiparasitic activity that led a few hits especially nucleoside-thiopyranoside conjugates, which are highly effective against Pf 3D7 and Pf RKL-9 strains in submicromolar concentration. One adenosine derivative and four pyrimidine nucleoside analogues significantly reduced the parasite burden in mouse models infected with Plasmodium berghei ANKA. Importantly, no significant hemolysis and cytotoxicity towards human cell line (RAW) was observed for the hits, suggesting their safety profile. Preliminary research suggested that these thiosugar-nucleoside conjugates could be used to accelerate the antimalarial drug development pipeline and thus deserve further investigation. LA - English DB - MTMT ER - TY - JOUR AU - Godoy, Andre Schutzer AU - Nakamura, Aline Minalli AU - Douangamath, Alice AU - Song, Yun AU - Noske, Gabriela Dias AU - Gawriljuk, Victor Oliveira AU - Fernandes, Rafaela Sachetto AU - Pereira, Humberto D Muniz AU - Oliveira, Ketllyn Irene Zagato AU - Fearon, Daren AU - Dias, Alexandre AU - Krojer, Tobias AU - Fairhead, Michael AU - Powell, Alisa AU - Dunnet, Louise AU - Brandao-Neto, Jose AU - Skyner, Rachael AU - Chalk, Rod AU - Bajusz, Dávid AU - Bege, Miklós AU - Borbás, Anikó AU - Keserű, György Miklós AU - von Delft, Frank AU - Oliva, Glaucius TI - Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - 10 SP - 5255 EP - 5270 PG - 16 SN - 0305-1048 DO - 10.1093/nar/gkad314 UR - https://m2.mtmt.hu/api/publication/33802561 ID - 33802561 AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors. LA - English DB - MTMT ER - TY - JOUR AU - Vass, Virág AU - Szabó, Erzsébet AU - Bakai-Bereczki, Ilona AU - Debreczeni, Nóra AU - Borbás, Anikó AU - Herczegh, Pál AU - Tósaki, Árpád TI - Reperfusion-induced injury and the effects of the dithioacetate type hydrogen sulfide donor ibuprofen derivative, BM-88, in isolated rat hearts JF - EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES J2 - EUR J PHARM SCI VL - 185 PY - 2023 SN - 0928-0987 DO - 10.1016/j.ejps.2023.106449 UR - https://m2.mtmt.hu/api/publication/33768628 ID - 33768628 N1 - Export Date: 11 October 2023 CODEN: EPSCE LA - English DB - MTMT ER -