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  - Bege, Miklós
AU  - Herczeg, Mihály
AU  - Bakai-Bereczki, Ilona
AU  - Debreczeni, Nóra
AU  - Bényei, Attila Csaba
AU  - Herczegh, Pál
AU  - Borbás, Anikó
TI  - Triaza-tricyclanos – synthesis of a new class of tricyclic nucleoside analogues by stereoselective cascade cyclocondensation
JF  - ORGANIC & BIOMOLECULAR CHEMISTRY
J2  - ORG BIOMOL CHEM
VL  - 21
PY  - 2023
IS  - 10
SP  - 2213
EP  - 2219
PG  - 7
SN  - 1477-0520
DO  - 10.1039/D3OB00154G
UR  - https://m2.mtmt.hu/api/publication/33657380
ID  - 33657380
AB  - Conformationally constrained tricyclic morpholino-nucleosides containing three new chirality centers were prepared with full stereoselectivity, through two consecutive hemiaminal-imidazolidine cascade reactions.
LA  - English
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Debreczeni, Nóra
AU  - Hotzi, Judit
AU  - Bege, Miklós
AU  - Lovas, Miklós
AU  - Mező, Erika
AU  - Bakai-Bereczki, Ilona
AU  - Herczegh, Pál
AU  - Kiss, Loránd
AU  - Borbás, Anikó
TI  - N‐Fluoroalkylated Morpholinos – a New Class of Nucleoside Analogues
JF  - CHEMISTRY-A EUROPEAN JOURNAL
J2  - CHEM-EUR J
VL  - 29
PY  - 2023
IS  - 11
PG  - 15
SN  - 0947-6539
DO  - 10.1002/chem.202203248
UR  - https://m2.mtmt.hu/api/publication/33297309
ID  - 33297309
N1  - Funding details: RRF‐2.3.1‐21‐2022‐00010            
            Funding details: European Regional Development Fund, ERDF, GINOP‐2.3.4‐15‐2020‐00008            
            Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, K‐142266, NKFIH/OTKA K‐132870            
            Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA            
            Funding text 1: The authors gratefully acknowledge financial support from the National Research, Development and Innovation Office of Hungary (NKFIH/OTKA K‐132870 and K‐142266). N. D. acknowledges the support of the ÚNKP‐22‐4 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund. The research was supported by the EU and co‐financed by the European Regional Development Fund under the project GINOP‐2.3.4‐15‐2020‐00008. This work was also supported by the National Laboratory of Virology, project no. RRF‐2.3.1‐21‐2022‐00010. The authors gratefully thank Prof. Gyula Batta for his help in the F NMR measurements. 19
LA  - English
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Bege, Miklós
TI  - Nukleozidanalóg hatóanyagok használata a Covid-19 kezelésére
JF  - GYÓGYSZERÉSZET
J2  - GYÓGYSZERÉSZET
VL  - 66
PY  - 2022
IS  - 5
SP  - 232
EP  - 235
PG  - 4
SN  - 0017-6036
UR  - https://m2.mtmt.hu/api/publication/33663027
ID  - 33663027
LA  - Hungarian
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Bege, Miklós
TI  - Géncsendesítő gyógyszerek I. - Bevezetés a természetes és mesterséges nukleinsavak világába
JF  - GYÓGYSZERÉSZET
J2  - GYÓGYSZERÉSZET
VL  - 66
PY  - 2022
IS  - 8
SP  - 395
EP  - 400
PG  - 6
SN  - 0017-6036
UR  - https://m2.mtmt.hu/api/publication/33663026
ID  - 33663026
LA  - Hungarian
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Bege, Miklós
TI  - Géncsendesítő Gyógyszerek II: - Transzlációgátló antiszenz oligonukleotidok
JF  - GYÓGYSZERÉSZET
J2  - GYÓGYSZERÉSZET
VL  - 16
PY  - 2022
IS  - 09
SP  - 451
EP  - 453
PG  - 3
SN  - 0017-6036
UR  - https://m2.mtmt.hu/api/publication/33170957
ID  - 33170957
LA  - Hungarian
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Bege, Miklós
AU  - Kiss, Alexandra
AU  - Bakai-Bereczki, Ilona
AU  - Hodek, Jan
AU  - Polyák, Lenke
AU  - Szemán-Nagy, Gábor
AU  - Naesens, Lieve
AU  - Weber, Jan
AU  - Borbás, Anikó
TI  - Synthesis and Anticancer and Antiviral Activities of C-2′-Branched Arabinonucleosides
JF  - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
J2  - INT J MOL SCI
VL  - 23
PY  - 2022
IS  - 20
PG  - 23
SN  - 1661-6596
DO  - 10.3390/ijms232012566
UR  - https://m2.mtmt.hu/api/publication/33170331
ID  - 33170331
N1  - Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, Debrecen, 4032, Hungary            
            Institute of Healthcare Industry, University of Debrecen, Nagyerdei krt 98, Debrecen, 4032, Hungary            
            MTA-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, Debrecen, 4032, Hungary            
            Department of Biotechnology and Microbiology, University of Debrecen, Egyetem tér 1, Debrecen, 4032, Hungary            
            National Laboratory of Virology, University of Pécs, Ifjúság útja 20, Pécs, 7624, Hungary            
            Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2, Prague, CZ-16000, Czech Republic            
            Rega Institute for Medical Research, KU Leuven, Leuven, B-3000, Belgium            
            Export Date: 09 January 2024; Cited By: 1; Correspondence Address: A. Borbás; Department of Pharmaceutical Chemistry, University of Debrecen, Debrecen, Egyetem tér 1, 4032, Hungary; email: borbas.aniko@pharm.unideb.hu
AB  - d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2’ position were prepared from the corresponding 3’,5’-O-silylene acetal-protected nucleoside 2’-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay. Three pyrimidine nucleosides containing C2’-butylsulfanylmethyl or -acetylthiomethyl groups showed promising cytotoxicity at low micromolar concentrations with good selectivity towards tumor cells. SAR analysis using a methyl β-d-arabinofuranoside reference compound showed that the silyl-protecting group, the nucleobase and the corresponding C2’ substituent are crucial for the cell growth inhibitory activity. The effects of the three most active nucleoside analogues on parameters indicative of cytotoxicity, such as cell size, division time and cell generation time, were investigated by near-infrared live cell imaging, which showed that the 2’-acetylthiomethyluridine derivative induced the most significant functional and morphological changes. Some nucleoside analogues also exerted anti-SARS-CoV-2 and/or anti-HCoV-229E activity with low micromolar EC50 values; however, the antiviral activity was always accompanied by significant cytotoxicity.
LA  - English
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Óvári, Ignác
AU  - Szilágyi, Viktória
AU  - Viczján, Gábor
AU  - Lampé, Nóra
AU  - Bege, Miklós
AU  - Borbás, Anikó
AU  - Herczeg, Pál
AU  - Juhász, Béla
AU  - Gesztelyi, Rudolf
AU  - Erdei, Tamás Dániel
TI  - Egy újonnan szintetizált adenozin analóg, a hipoxantin-triciklánó hatása izolált patkány bal és jobb pitvaron
JF  - EGÉSZSÉGÜGYI INNOVÁCIÓS SZEMLE
J2  - EÜ INNOV SZLE
VL  - 1
PY  - 2022
IS  - 1
SP  - 9
EP  - 16
PG  - 8
SN  - 2939-6026
DO  - 10.56626/egis.v1i1.7059
UR  - https://m2.mtmt.hu/api/publication/33037647
ID  - 33037647
AB  - A hipoxantin-triciklánó egy a DE GYTK Gyógyszerészi Kémia Tanszéken szintetizált adenozin analóg, melyben az adenint hipoxantin, a ribózt pedig egy kondenzált triciklikus molekularész helyettesíti. Munkánk során a hipoxantin-triciklánó hatását vizsgáltuk a pitvari myocardium A1 adenozinerg rendszerére, melynek (pozitív agonista általi) aktivációja számos protektív folyamatért, köztük negatív trop hatásokért felelős.

A vizsgálatokat hím Wistar patkányokból izolált bal pitvari fülcsén és teljes jobb pitvaron végeztük. A preparátumokat 95% O2 és 5% CO2 gázeleggyel szellőztetett, 36°C-os Krebs oldatot tartalmazó szervkádakban függesztettük fel 10 mN alapfeszülés mellett. A bal pitvarokat állandó frekvencián ingereltük (3 Hz; 1 ms; 1-1,5 V), míg a jobb pitvarok spontán húzódtak össze. A preparátumokon az adenozin és a hipoxantin-triciklánó inotrop és chronotrop hatását vizsgáltuk külön-külön és együtt, továbbá CPX (8-cyclopentyl-1,3-dipropylxanthine; reverzibilis A1 adenozin receptor antagonista) hiányában és jelenlétében.

Eredményeink alapján az adenozin mind a bal, mind a jobb pitvarokon hasonló mértékű, erőteljes negatív inotrop hatást fejtett ki. A hipoxantin-triciklánó ezzel szemben mérsékelt pozitív inotrop hatást váltott ki, ami hasonló mértékű volt a jobb és a bal pitvarokon. Az inotropia alakulásával összhangban, az adenozin markánsan negatív, míg a hipoxantin-triciklánó kismértékben pozitív chronotrop hatásúnak bizonyult a jobb pitvarokon. A CPX erősen (és szignifikánsan) gátolta az adenozin hatásait, de csak kisebb mértékű (és nem szignifikáns) gátlást hozott létre a hipoxantin-triciklánó hatásaival szemben. A hipoxantin-triciklánó hatásai teljes mértékben áttörhetőek voltak adenozinnal. Mindezek hátterében felvethető, hogy az adenozin könnyen le tudja szorítani a hipoxantin-triciklánót az A1 adenozin receptorról, de (ehelyett vagy emellett) elképzelhető, hogy a hipoxantin-triciklánó az A1 adenozin receptortól független útvonalon is hat. A hipoxantin-triciklánó tehát feltehetően a myocardialis A1 adenozin receptor reverzibilis, ortosztérikus, inverz agonistája, melynek ugyanakkor más támadáspontja is lehet a myocardiumban.

The  hypoxanthine-tricyclano  is  a  new  adenosine  analogue,  in  which  adenine  and  ribose  are  replaced  by hypoxanthine and a fused tricyclic moiety, respectively, synthetized in the Department of Pharma-ceutical Chemistry (Faculty of Pharmacy, University of Debrecen). In the current study, we investigated the effect of hypoxanthine-tricyclano on the A1 adenosinergic system of the rat atrial myocardium, ac-tivation of which (by a positive agonist) is responsible for several protective actions, including negative tropic effects.The left atrial auricle and the whole right atrium were isolated from male Wistar rats and mounted at 10   mN resting tension in 10 mL vertical organ chambers containing Krebs solution (36 °C) oxygenated with 95% O2 and 5% CO2. Left atria were paced (3 Hz, 1 ms, 1-2 V), while right atria worked spontaneous-ly. The inotropic and chronotropic effects of adenosine and hypoxanthine-tricyclano were investigated (separately and in combination), in the absence and presence of CPX (8-cyclopenty l-1,3-dipropylxan-thine), a reversible A1 adenosine receptor antagonist.Adenosine elicited a strong negative inotropic effect on both the left and right atria (to a similar extent). In contrast, hypoxanthine-tricyclano produced a moderate positive inotropic effect in the left and right atria (also to a similar extent). In consistent with the inotropic effects, adenosine exerted a substantial negative chronotropic effect, and hypoxanthine-tricyclano elicited a slight positive chronotropic effect in the right atria. CPX strongly (and statistically significantly) blunted the effects of adenosine but it pro-duced only a minor (and not significant) inhibition against actions of hypoxanthine-tricyclano. In addi-tion, the effects of hypoxanthine-tricyclano were completely surmountable with adenosine. This can be explained by supposing that adenosine can easily displace hypoxanthine-tricyclano from their receptor, and, alternatively or in addition, that hypoxanthine-tricyclano may also act in a pathway independent from  the  A1  adenosine  receptor.  Thus,  hypoxanthine-tricyclano  is  probably  a  reversible,  orthosteric,  inverse  agonist  of  the  myocardial  A1  adenosine  receptor  that  might  also  have  another  target  in  the  myocardium.
LA  - Hungarian
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Bege, Miklós
AU  - Borbás, Anikó
TI  - The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides
JF  - PHARMACEUTICALS
J2  - PHARMACEUTICALS-BASE
VL  - 15
PY  - 2022
IS  - 8
PG  - 39
SN  - 1424-8247
DO  - 10.3390/ph15080909
UR  - https://m2.mtmt.hu/api/publication/33025875
ID  - 33025875
AB  - Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.
LA  - English
DB  - MTMT
ER  -