TY - JOUR AU - Ábrányi-Balogh, Péter AU - Bajusz, Dávid AU - Orgován, Zoltán AU - Keeley, Aaron Brian AU - Petri, László AU - Péczka, Nikolett AU - Szalai, Tibor Viktor AU - Pálfy, Gyula AU - Gadanecz, Márton AU - Grant, Emma K. AU - Imre, Tímea AU - Takács, Tamás AU - Randelovic, Ivan AU - Baranyi, Marcell AU - Marton, András Dénes AU - Schlosser, Gitta (Vácziné) AU - Ashraf, Qirat F. AU - de Araujo, Elvin D. AU - Karancsi, Tamás AU - Buday, László AU - Tóvári, József AU - Perczel, András AU - Bush, Jacob T. AU - Keserű, György Miklós TI - Mapping protein binding sites by photoreactive fragment pharmacophores JF - COMMUNICATIONS CHEMISTRY J2 - COMMUN CHEM VL - 7 PY - 2024 IS - 1 PG - 13 SN - 2399-3669 DO - 10.1038/s42004-024-01252-w UR - https://m2.mtmt.hu/api/publication/35160281 ID - 35160281 N1 - Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary National Drug Research and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Department of Inorganic and Analytical Chemistry, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Laboratory of Structural Chemistry and Biology & amp; HUN-REN–ELTE Protein Modelling Research Group, Eötvös Loránd University, Budapest, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, Hungary GlaxoSmithKline, Hertfordshire, United Kingdom MS Metabolomics Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Signal Transduction and Functional Genomics Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary National Tumor Biology Laboratory and Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary KINETO Lab Ltd, Budapest, Hungary Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary Department of Chemical and Environmental Process Engineering, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Waters Research Center, Budapest, Hungary MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Eötvös Loránd University, Budapest, Hungary Department of Chemical & amp; Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada Centre for Medicinal Chemistry, University of Toronto at Mississauga, Mississauga, ON, Canada Export Date: 26 August 2024 Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Hungary; email: keseru.gyorgy@ttk.hu AB - Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas G12D protein, and the yet unliganded N -terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets. LA - English DB - MTMT ER - TY - JOUR AU - Keeley, Aaron Brian AU - Kopranovic, Aleksandra AU - Di Lorenzo, Vincenzo AU - Ábrányi-Balogh, Péter AU - Jänsch, Niklas AU - Lai, Linh N. AU - Petri, László AU - Orgován, Zoltán AU - Pölöske, Daniel AU - Orlova, Anna AU - Németh, András György AU - Desczyk, Charlotte AU - Imre, Timea AU - Bajusz, Dávid AU - Moriggl, Richard AU - Meyer-Almes, Franz-Josef AU - Keserű, György Miklós TI - Electrophilic MiniFrags Revealed Unprecedented Binding Sites for Covalent HDAC8 Inhibitors JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM VL - 67 PY - 2024 IS - 1 SP - 572 EP - 585 PG - 14 SN - 0022-2623 DO - 10.1021/acs.jmedchem.3c01779 UR - https://m2.mtmt.hu/api/publication/34445373 ID - 34445373 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Müegyetem rkp. 3., Budapest, H-1111, Hungary National Laboratory for Drug Research and Development, Budapest, H-1117, Hungary Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, Darmstadt, 64295, Germany Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, 1210, Austria MS Metabolomics Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, Budapest, H-1117, Hungary Export Date: 14 March 2024 CODEN: JMCMA Correspondence Address: Meyer-Almes, F.-J.; Department of Chemical Engineering and Biotechnology, Haardtring 100, Germany; email: franz-josef.meyer-almes@h-da.de Correspondence Address: Keserü, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt 2, Hungary; email: keseru.gyorgy@ttk.hu AB - Screening of ultra-low-molecular weight ligands (MiniFrags) successfully identified viable chemical starting points for a variety of drug targets. Here we report the electrophilic analogues of MiniFrags that allow the mapping of potential binding sites for covalent inhibitors by biochemical screening and mass spectrometry. Small electrophilic heterocycles and their N-quaternized analogues were first characterized in the glutathione assay to analyze their electrophilic reactivity. Next, the library was used for systematic mapping of potential covalent binding sites available in human histone deacetylase 8 (HDAC8). The covalent labeling of HDAC8 cysteines has been proven by tandem mass spectrometry measurements, and the observations were explained by mutating HDAC8 cysteines. As a result, screening of electrophilic MiniFrags identified three potential binding sites suitable for the development of allosteric covalent HDAC8 inhibitors. One of the hit fragments was merged with a known HDAC8 inhibitor fragment using different linkers, and the linker length was optimized to result in a lead-like covalent inhibitor. © 2023 The Authors. Published by American Chemical Society LA - English DB - MTMT ER - TY - JOUR AU - Kollár, Levente AU - Grabrijan, Katarina AU - Hrast Rambaher, Martina AU - Bozovičar, Krištof AU - Imre, Tímea AU - Ferenczy, György AU - Gobec, Stanislav AU - Keserű, György Miklós TI - Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents JF - JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY J2 - J ENZYM INHIB MED CH VL - 39 PY - 2024 IS - 1 PG - 14 SN - 1475-6366 DO - 10.1080/14756366.2024.2305833 UR - https://m2.mtmt.hu/api/publication/34718013 ID - 34718013 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia MS Metabolomics Research Group, Research Centre for Natural Sciences, Budapest, Hungary Export Date: 8 March 2024 CODEN: JEIMA Correspondence Address: Keserű, G.M.; Department of Organic Chemistry and Technology, Műegyetem rkp. 3., Hungary; email: keseru.gyorgy@ttk.hu Funding details: RRF-2.3.1-21-2022-00015 Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS, N1-0169, P1-0208 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFI, K135335 Funding details: Richter Gedeon Talentum Alapítvány Funding text 1: We thank Dr. Andrea Dessen (IBS, Grenoble) for donation of PBP1b plasmid and Dr. Pál Szabó for HRMS measurements. This study was supported by National Research, Development and Innovation Office Grants K135335, and by the National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015). Funding text 2: This research was funded by the National Research Development and Innovation Office (Grant Numbers: SNN 135335), Slovenian Research Agency (ARRS) Research Core Funding P1-0208, grant N1-0169 and a PhD grant to K.G. L.K. is supported by the Gedeon Richter Talentum Foundation and the József Varga Foundation and Javna Agencija za Raziskovalno Dejavnost RS. We thank Dr. Andrea Dessen (IBS, Grenoble) for donation of PBP1b plasmid and Dr. Pál Szabó for HRMS measurements. This study was supported by National Research, Development and Innovation Office Grants K135335, and by the National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015). LA - English DB - MTMT ER - TY - JOUR AU - Krámos, Balázs AU - Hadady, Zsuzsa AU - Makó, Attila AU - Szántó, Gábor AU - Felföldi, Nóra AU - Magdó, Ildikó AU - Bobok, Amrita Ágnes AU - Bata, Imre AU - Román, Viktor AU - Visegrády, András AU - Keserű, György Miklós AU - Greiner, István AU - Éles, János TI - Novel-Type GABA B PAMs: Structure–Activity Relationship in Light of the Protein Structure JF - ACS MEDICINAL CHEMISTRY LETTERS J2 - ACS MED CHEM LETT PY - 2024 SN - 1948-5875 DO - 10.1021/acsmedchemlett.3c00560 UR - https://m2.mtmt.hu/api/publication/34720633 ID - 34720633 LA - English DB - MTMT ER - TY - CHAP AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Keserű, György Miklós ED - Ramaswamy, Vijayan ED - Poongavanam, Vasanthanathan TI - Free Energy Calculations in Covalent Drug Design T2 - Computational Drug Discovery PB - Wiley SN - 9783527840748 PY - 2024 SP - 561 EP - 578 PG - 18 DO - 10.1002/9783527840748.ch23 UR - https://m2.mtmt.hu/api/publication/34535308 ID - 34535308 LA - English DB - MTMT ER - TY - JOUR AU - Mihalovits, Levente Márk AU - Kollár, Levente AU - Bajusz, Dávid AU - Knez, Damijan AU - Bozovičar, Krištof AU - Imre, Timea AU - Ferenczy, György AU - Gobec, Stanislav AU - Keserű, György Miklós TI - Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones JF - CHEMPHYSCHEM: A EUROPEAN JOURNAL OF CHEMICAL PHYSICS AND PHYSICAL CHEMISTRY J2 - CHEMPHYSCHEM VL - 25 PY - 2024 IS - 1 SN - 1439-4235 DO - 10.1002/cphc.202300596 UR - https://m2.mtmt.hu/api/publication/34223252 ID - 34223252 N1 - Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., Budapest, 1111, Hungary Department of Medicinal Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana, 1000, Slovenia MS Metabolomics Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary Export Date: 24 November 2023 CODEN: CPCHF Correspondence Address: Bajusz, D.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, Hungary; email: bajusz.david@ttk.hu Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, Hungary; email: keseru.gyorgy@ttk.hu AB - Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS‐CoV‐2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in‐house, cysteine‐targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules. LA - English DB - MTMT ER - TY - JOUR AU - Morales, Paula AU - Scharf, Magdalena M. AU - Bermudez, Marcel AU - Egyed, Attila AU - Franco, Rafael AU - Hansen, Olivia K. AU - Jagerovic, Nadine AU - Jakubík, Jan AU - Keserű, György Miklós AU - Kiss, Dóra Judit AU - Kozielewicz, Pawel AU - Larsen, Olav AU - Majellaro, Maria AU - Mallo‐Abreu, Ana AU - Navarro, Gemma AU - Prieto‐Díaz, Rubén AU - Rosenkilde, Mette M. AU - Sotelo, Eddy AU - Stark, Holger AU - Werner, Tobias AU - Wingler, Laura M. TI - Progress on the development of Class A GPCR‐biased ligands JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL PY - 2024 SN - 0007-1188 DO - 10.1111/bph.17301 UR - https://m2.mtmt.hu/api/publication/35265081 ID - 35265081 AB - Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR‐biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. LA - English DB - MTMT ER - TY - JOUR AU - Németh, András György AU - Kollár, Levente AU - Németh, K. AU - Schlosser, Gitta (Vácziné) AU - Minus, Annamária AU - Keserű, György Miklós TI - On-DNA Synthesis of Multisubstituted Indoles JF - ORGANIC LETTERS J2 - ORG LETT VL - 26 PY - 2024 IS - 13 SP - 2517 EP - 2522 PG - 6 SN - 1523-7060 DO - 10.1021/acs.orglett.3c03602 UR - https://m2.mtmt.hu/api/publication/34492242 ID - 34492242 N1 - Export Date: 10 January 2024; Cited By: 0; Correspondence Address: G.M. Keserű; Medicinal Chemistry Research Group, HUN-REN Research Centre for Natural Sciences, Budapest, H-1117, Hungary; email: keseru.gyorgy@ttk.hu; CODEN: ORLEF AB - The increasing role of the DNA-encoded library technology in early phase drug discovery represents a significant demand for DNA-compatible synthetic methods for therapeutically relevant heterocycles. Herein, we report the first on-DNA synthesis of multisubstituted indoles via a cascade reaction of Sonogashira coupling and intramolecular ring closure. Further functionalization by Suzuki coupling at the third position exploits a diverse chemical space. The high fidelity of the method also enabled the construction of an indole-based mock library. © 2023 The Authors. Published by American Chemical Society. LA - English DB - MTMT ER - TY - JOUR AU - Pándy-Szekeres, Gáspár AU - Taracena Herrera, Luis P AU - Caroli, Jimmy AU - Kermani, Ali A AU - Kulkarni, Yashraj AU - Keserű, György Miklós AU - Gloriam, David E TI - GproteinDb in 2024: new G protein-GPCR couplings, AlphaFold2-multimer models and interface interactions JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 52 PY - 2024 IS - D1 SP - D466 EP - D475 SN - 0305-1048 DO - 10.1093/nar/gkad1089 UR - https://m2.mtmt.hu/api/publication/34405999 ID - 34405999 AB - G proteins are the major signal proteins of ∼800 receptors for medicines, hormones, neurotransmitters, tastants and odorants. GproteinDb offers integrated genomic, structural, and pharmacological data and tools for analysis, visualization and experiment design. Here, we present the first major update of GproteinDb greatly expanding its coupling data and structural templates, adding AlphaFold2 structure models of GPCR–G protein complexes and advancing the interactive analysis tools for their interfaces underlying coupling selectivity. We present insights on coupling agreement across datasets and parameters, including constitutive activity, agonist-induced activity and kinetics. GproteinDb is accessible at https://gproteindb.org. LA - English DB - MTMT ER - TY - JOUR AU - Papp, H. AU - Tóth, Emese AU - Bóvári-Biri, J. AU - Bánfai, K. AU - Juhász, P. AU - Mahdi, M. AU - Russo, L.C. AU - Bajusz, Dávid AU - Sipos, Adrienn AU - Petri, László AU - Szalai, Tibor Viktor AU - Kemény, Ágnes AU - Madai, M. AU - Kuczmog, A. AU - Batta, Gyula AU - Mózner, Orsolya AU - Vaskó, Dorottya AU - Hirsch, Edit AU - Bohus, P. AU - Méhes, G. AU - Tőzsér, J. AU - Curtin, N.J. AU - Helyes, Zsuzsanna AU - Tóth, A. AU - Hoch, N.C. AU - Jakab, F. AU - Keserű, György Miklós AU - Pongrácz, J.E. AU - Bay, Péter TI - The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19 JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL PY - 2024 PG - 22 SN - 0007-1188 DO - 10.1111/bph.17305 UR - https://m2.mtmt.hu/api/publication/35196297 ID - 35196297 N1 - National Laboratory of Virology, University of Pécs, Pécs, Hungary Institute of Biology, Faculty of Sciences, University of Pécs, Pécs, Hungary Szentagothai Research Centre, University of Pécs, Pécs, Hungary Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary HUN-REN-DE Cell Biology and Signaling Research Group, Debrecen, Hungary Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pécs, Pécs, Hungary Department of Pathology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary Department of Inorganic and Analytical Chemistry, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Department of Pharmacology and Pharmacotherapy, Medical School & Centre for Neuroscience, University of Pécs, Pécs, Hungary Department of Medical Biology, Medical School, Pécs, Hungary Department of Organic Chemistry, Faculty of Science and Technology, University of Debrecen, Debrecen, Hungary Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary Erzsébet Hospital, Sátoraljaújhely, Hungary Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom Hungarian Research Network, Chronic Pain Research Group, University of Pécs, Pécs, Hungary National Laboratory for Drug Research and Development, Budapest, Hungary Section of Clinical Physiology, Department of Cardiology, University of Debrecen, Debrecen, Hungary MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Export Date: 9 September 2024 CODEN: BJPCB Correspondence Address: Bai, P.; Faculty of Medicine, Egyetem tér 1., Hungary; email: baip@med.unideb.hu Funding details: Debreceni Egyetem, DE Funding details: Innovációs és Technológiai Minisztérium Funding details: Magyar Tudományos Akadémia, MTA Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, SNN135335, K142141, K135150, TKP2021‐NVA‐07, FK146852, TKP‐2021‐EGA‐13, PD142301, FK146063, RRF‐2.3.1‐21‐2022‐00010, 2020‐1.1.2‐PIACI‐KFI‐2020‐00039, TKP2021‐EGA‐10, K132623 Funding text 1: The work was supported by grants from the NKFIH (K132623, K142141, K135150, SNN135335, PD142301, FK146852, TKP2021\\u2010EGA\\u201010, TKP\\u20102021\\u2010EGA\\u201013, TKP2021\\u2010EGA\\u201019, TKP2021\\u2010EGA\\u201020, TKP2021\\u2010NVA\\u201007, RRF\\u20102.3.1\\u201021\\u20102022\\u201000010, FK146063, 2020\\u20101.1.2\\u2010PIACI\\u2010KFI\\u20102020\\u201000039). The Projects no. TKP2021\\u2010EGA\\u201010, TKP\\u20102021\\u2010EGA\\u201013, TKP2021\\u2010EGA\\u201019 and TKP2021\\u2010EGA\\u201020 were implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021\\u2010EGA funding scheme. Project no. TKP2021\\u2010NVA\\u201007 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021\\u2010NVA funding scheme. The POST\\u2010COVID2021\\u201033 grant to PB was from the Hungarian Academy of Sciences. FAPESP grants 2018/18007\\u20105 and 2020/05317\\u20106 were to NH. The research was performed in collaboration with Cell and Tissue Culture Core Facility at the Szentagothai Research Centre of the University of Pecs. The work of D.B. and A.S. were supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP\\u2010 21\\u20105 New National Excellence Program of the Ministry for Innovation and Technology. Prepared with the professional support of the Doctoral Student Scholarship Program of the Co\\u2010operative Doctoral Program of the Ministry of Innovation and Technology financed from the National Research, Development and Innovation Fund (to OM). The authors are grateful to Dr. Bal\\u00E1zs Sarkadi (Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary) for his support and the critical revision of the manuscript. This project received funding from the HUN\\u2010REN Hungarian Research Network. Supported by the University of Debrecen Program for Scientific Publication. AB - Background and Purpose: To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID-19. Experimental Approach: The effects of PARP inhibitors on virus uptake were assessed in cell-based experiments using multiple variants of SARS-CoV-2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti-inflammatory properties of rucaparib were demonstrated in cell-based models upon challenging with recombinant spike protein or SARS-CoV-2 RNA vaccine. Key Results: We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID-19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS-CoV-2 infection rate through binding to the conserved 493–498 amino acid region located in the spike-ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA-induced overexpression of cytokines was down-regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations. Conclusion and Implications: These results point towards repurposing rucaparib for treating inflammatory responses in COVID-19. © 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. LA - English DB - MTMT ER - TY - JOUR AU - Péczka, Nikolett AU - Randelovic, Ivan AU - Orgován, Zoltán AU - Csorba, Noémi AU - Egyed, Attila AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Gadanecz, Márton AU - Perczel, András AU - Tóvári, József AU - Schlosser, Gitta (Vácziné) AU - Takács, Tamás AU - Mihalovits, Levente Márk AU - Ferenczy, György AU - Buday, László AU - Keserű, György Miklós TI - Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors : A Case Study on KRasG12C JF - ACS CHEMICAL BIOLOGY J2 - ACS CHEM BIOL VL - 19 PY - 2024 IS - 8 SP - 1743 EP - 1756 PG - 14 SN - 1554-8929 DO - 10.1021/acschembio.4c00217 UR - https://m2.mtmt.hu/api/publication/35134356 ID - 35134356 N1 - Medicinal Chemistry Research Group, National Drug Discovery and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, 1111, Hungary Department of Experimental Pharmacology, The National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary Protein Modeling Research Group, Laboratory of Structural Chemistry and Biology, ELTE Institute of Chemistry, Budapest, 1117, Hungary Hevesy György PhD School of Chemistry, Eötvös Loránd University, Pázmány Péter sétány. 1/A, Budapest, 1117, Hungary MTA-ELTE “Lendület”, Ion Mobility Mass Spectrometry Research Group, Budapest, 1117, Hungary HUN-REN Research Centre for Natural Sciences, Signal Transduction and Functional Genomics Research Group, Budapest, 1117, Hungary Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, 1117, Hungary Export Date: 5 August 2024 CODEN: ACBCC Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Hungary; email: keseru.gyorgy@ttk.hu Funding details: Ministry of Innovation, Science and Technology, MOST Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA Funding details: TKP2021-EGA-20, TKP2021-EGA-44 Funding details: RRF-2.3.1-21-2022-00015 Funding details: 2022-2.1.1-NL-2022-00010 Funding details: National Research, Development and Innovation Office, NVKP_16-1-2016-0020 Funding text 1: The authors gratefully acknowledge the synthetic contribution of S. Csana\\u0301dy and the MS measurement support of P. Szabo\\u0301. This work has been supported by the National Research, Development and Innovation Office under the contract numbers NVKP_16-1-2016-0020 and 2020-1.1.6-JO\\u0308VO\\u030B, as well as the Thematic Excellence Program under project \\u201CSzintPlusz\\u201D and by the National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015). The research was also funded by the National Laboratories Excellence program (under the National Tumor Biology Laboratory Project (2022-2.1.1-NL-2022-00010)) and the Hungarian Thematic Excellence Program (TKP2021-EGA-20, TKP2021-EGA-44). T. T. was supported by the KDP-2021 Program of the Ministry of Innovation and Technology from the source of the National Research, Development and Innovation Fund. AB - Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions. Noncovalent and covalent binding steps can be characterized by an equilibrium dissociation constant (KI) and a reaction rate constant (kinact), respectively, and they are affected by both the warhead and the scaffold of the ligand. The relative contribution of these two steps was investigated on a prototypic drug target KRASG12C, an oncogenic mutant of KRAS. We used a synthetically more accessible nonchiral core derived from ARS-1620 that was equipped with four different warheads and a previously described KRAS-specific basic side chain. Combining these structural changes, we have synthesized novel covalent KRASG12C inhibitors and tested their binding and biological effect on KRASG12C by various biophysical and biochemical assays. These data allowed us to dissect the effect of scaffold and warhead on the noncovalent and covalent binding event. Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRASG12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents. LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Pásztor, Bettina AU - Ábrányi-Balogh, Péter AU - Petri, László AU - Imre, Tímea AU - Simon, József AU - Tátrai, Enikő AU - Várady, György AU - Tóvári, József AU - Szijj, Peter A AU - Keserű, György Miklós TI - Site-Selective Antibody Conjugation with Dibromopyrazines JF - BIOCONJUGATE CHEMISTRY J2 - BIOCONJUGATE CHEM VL - 35 PY - 2024 IS - 9 SP - 1373 EP - 1379 PG - 7 SN - 1043-1802 DO - 10.1021/acs.bioconjchem.4c00296 UR - https://m2.mtmt.hu/api/publication/35176724 ID - 35176724 N1 - Funding Agency and Grant Number: Pharma Lab [2018-1.3.1-VKE-2018-00032, RRF-2.3.1-21-2022-00015, TKP2021-EGA-44]; National Tumor Biology Laboratory [NLP-17]; National Office of Research, Innovation and Technology [PD124598, PD143427]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund [UNKP-23-4] Funding text: This work was supported by the 2018-1.3.1-VKE-2018-00032, Pharma Lab RRF-2.3.1-21-2022-00015, TKP2021-EGA-44, National Tumor Biology Laboratory (NLP-17), PD124598, and PD143427 grants of the National Office of Research, Innovation and Technology. P.A.-B. is grateful for the support of the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. L.P. was supported by the UNKP-23-4 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund. The authors acknowledge the fruitful discussions with Prof. Vijay Chudasama (Department of Chemistry, University College London, London, U.K.). AB - In recent years, antibody conjugates have evolved as state-of-the-art options for diagnostic and therapeutic applications. During site-selective antibody conjugation, incomplete rebridging of antibody chains limits the homogeneity of conjugates and calls for the development of new rebridging agents. Herein, we report a dibromopyrazine derivative optimized to reach highly homogeneous conjugates rapidly and with high conversion on rebridging of trastuzumab, even providing a feasible route for antibody modification in acidic conditions. Furthermore, coupling a fluorescent dye and a cytotoxic drug resulted in effective antibody conjugates with excellent serum stability and in vitro selectivity, demonstrating the utility of the dibromopyrazine rebridging agent to produce on-demand future antibody conjugates for diagnostic or therapeutic applications. LA - English DB - MTMT ER - TY - JOUR AU - Bajusz, Dávid AU - Pándy-Szekeres, Gáspár AU - Takács, Ágnes AU - de Araujo, Elvin D AU - Keserű, György Miklós TI - SH2db, an information system for the SH2 domain JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - W1 SP - W542 EP - W552 SN - 0305-1048 DO - 10.1093/nar/gkad420 UR - https://m2.mtmt.hu/api/publication/33845452 ID - 33845452 N1 - Funding Agency and Grant Number: MSCA ITN ALLODD [956314]; National Research Development and Innovation Office of Hungary [K135150, RRF-2.3.1-21-2022-00015]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-22-5]; MSCA [956314, K135150] Funding text: MSCA ITN ALLODD [956314 to G.M.K.]; National Research Development and Innovation Office of Hungary [K135150, PharmaLab (RRF-2.3.1-21-2022-00015)]; the work of D.B. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and the 'UNKP-22-5 New National Excellence Program of the Ministry for Innovation and Technology. FUNDING for open access charge: MSCA-funded project 'ALLODD' [956314] and NRDIO grant [K135150]. AB - SH2 domains are key mediators of phosphotyrosine-based signalling, and therapeutic targets for diverse, mostly oncological, disease indications. They have a highly conserved structure with a central beta sheet that divides the binding surface of the protein into two main pockets, responsible for phosphotyrosine binding (pY pocket) and substrate specificity (pY + 3 pocket). In recent years, structural databases have proven to be invaluable resources for the drug discovery community, as they contain highly relevant and up-to-date information on important protein classes. Here, we present SH2db, a comprehensive structural database and webserver for SH2 domain structures. To organize these protein structures efficiently, we introduce (i) a generic residue numbering scheme to enhance the comparability of different SH2 domains, (ii) a structure-based multiple sequence alignment of all 120 human wild-type SH2 domain sequences and their PDB and AlphaFold structures. The aligned sequences and structures can be searched, browsed and downloaded from the online interface of SH2db (http://sh2db.ttk.hu), with functions to conveniently prepare multiple structures into a Pymol session, and to export simple charts on the contents of the database. Our hope is that SH2db can assist researchers in their day-to-day work by becoming a one-stop shop for SH2 domain related research. LA - English DB - MTMT ER - TY - JOUR AU - Csorba, Noémi AU - Ábrányi-Balogh, Péter AU - Keserű, György Miklós TI - Covalent fragment approaches targeting non-cysteine residues JF - TRENDS IN PHARMACOLOGICAL SCIENCES J2 - TRENDS PHARMACOL SCI VL - 44 PY - 2023 IS - 11 SP - 802 EP - 816 PG - 15 SN - 0165-6147 DO - 10.1016/j.tips.2023.08.014 UR - https://m2.mtmt.hu/api/publication/34160949 ID - 34160949 N1 - Export Date: 6 October 2023 CODEN: TPHSD Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar tudósok krt. 2, 1117, Hungary; email: keseru.gyorgy@ttk.hu 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 - Orgován, Zoltán AU - Péczka, Nikolett AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Randelovic, Ivan AU - Tóth, Szilárd AU - Szakács, Gergely AU - Nyíri, Kinga AU - Vértessy, Beáta (Grolmuszné) AU - Pálfy, Gyula AU - Vida, István AU - Perczel, András AU - Tóvári, József AU - Keserű, György Miklós TI - Covalent fragment mapping of KRasG12C revealed novel chemotypes with in vivo potency JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 250 PY - 2023 PG - 7 SN - 0223-5234 DO - 10.1016/j.ejmech.2023.115212 UR - https://m2.mtmt.hu/api/publication/33647485 ID - 33647485 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, and National Drug Discovery and Development Laboratory, Budapest, Hungary Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Budapest, Hungary KINETO Lab Ltd, Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Hungary Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, Budapest, Hungary MTA-ELTE Protein Modelling Research Group, Eötvös Loránd University, Budapest, Hungary Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary CODEN: EJMCA Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, 2 Magyar tudósok kӧrútja, Hungary; email: keseru.gyorgy@ttk.hu AB - G12C mutant KRas is considered druggable by allele-specific covalent inhibitors due to the nucleophilic character of the oncogenic mutant cysteine at position 12. Discovery of these inhibitors requires the optimization of both covalent and noncovalent interactions. Here, we report covalent fragment screening of our electrophilic fragment library of diverse non-covalent scaffolds equipped with 40 different electrophilic functionalities to identify fragments as suitable starting points targeting Cys12. Screening the library against KRasG12C using Ellman's free thiol assay, followed by protein NMR and cell viability assays, resulted in two potential inhibitor chemotypes. Characterization of these scaffolds in in vitro cellular- and in vivo xenograft models revealed them as promising starting points for covalent drug discovery programs. LA - English DB - MTMT ER - TY - JOUR AU - Pándy-Szekeres, Gáspár AU - Caroli, Jimmy AU - Mamyrbekov, Alibek AU - Kermani, Ali A. AU - Keserű, György Miklós AU - Kooistra, Albert J. AU - Gloriam, David E. TI - GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 51 PY - 2023 IS - D1 SP - D395 EP - D402 PG - 8 SN - 0305-1048 DO - 10.1093/nar/gkac1013 UR - https://m2.mtmt.hu/api/publication/33421768 ID - 33421768 AB - G protein-coupled receptors (GPCRs) are physiologically abundant signaling hubs routing hundreds of extracellular signal substances and drugs into intracellular pathways. The GPCR database, GPCRdb supports > 5000 interdisciplinary researchers every month with reference data, analysis, visualization, experiment design and dissemination. Here, we present our fifth major GPCRdb release setting out with an overview of the many resources for receptor sequences, structures, and ligands. This includes recently published additions of class D generic residue numbers, a comparative structure analysis tool to identify functional determinants, trees clustering GPCR structures by 3D conformation, and mutations stabilizing inactive/active states. We provide new state-specific structure models of all human non-olfactory GPCRs built using AlphaFold2-MultiState. We also provide a new resource of endogenous ligands along with a larger number of surrogate ligands with bioactivity, vendor, and physiochemical descriptor data. The one-stop-shop ligand resources integrate ligands/data from the ChEMBL, Guide to Pharmacology, PDSP Ki and PubChem database. The GPCRdb is available athttps://gpcrdb.org. LA - English DB - MTMT ER - TY - JOUR AU - Petri, László AU - Ábrányi-Balogh, Péter AU - Csorba, Noémi AU - Keeley, Aaron Brian AU - Simon, József AU - Randelovic, Ivan AU - Tóvári, József AU - Schlosser, Gitta (Vácziné) AU - Szabó, Dániel AU - Drahos, László AU - Keserű, György Miklós TI - Activation-Free Sulfonyl Fluoride Probes for Fragment Screening JF - MOLECULES J2 - MOLECULES VL - 28 PY - 2023 IS - 7 PG - 17 SN - 1420-3049 DO - 10.3390/molecules28073042 UR - https://m2.mtmt.hu/api/publication/33729477 ID - 33729477 N1 - Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary National Laboratory for Drug Research and Development, Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Szent Gellért tér 4, Budapest, 1111, Hungary Research Centre for Natural Sciences, MS Metabolomics Research Group, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary KINETO Lab Ltd, Zápor u. 55, Budapest, 1032, Hungary Department of Experimental Pharmacology and National Tumor Biology Laboratory, National Institute of Oncology, POB 21, Budapest, 1525, Hungary MTA-ELTE Lendület Ion Mobility Mass Spectrometry Research Group, Institute of Chemistry, ELTE Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, 1117, Hungary MS Proteomics Research Group, Research Centre for Natural Sciences, Magyar Tudósok Krt. 2, Budapest, 1117, Hungary Cited By :3 Export Date: 13 March 2024 CODEN: MOLEF Correspondence Address: Keserű, G.M.; Medicinal Chemistry Research Group, Magyar Tudósok Krt. 2, Hungary; email: keseru.gyorgy@ttk.hu AB - SuFEx chemistry is based on the unique reactivity of the sulfonyl fluoride group with a range of nucleophiles. Accordingly, sulfonyl fluorides label multiple nucleophilic amino acid residues, making these reagents popular in both chemical biology and medicinal chemistry applications. The reactivity of sulfonyl fluorides nominates this warhead chemotype as a candidate for an external, activation-free general labelling tag. Here, we report the synthesis and characterization of a small sulfonyl fluoride library that yielded the 3-carboxybenzenesulfonyl fluoride warhead for tagging tractable targets at nucleophilic residues. Based on these results, we propose that coupling diverse fragments to this warhead would result in a library of sulfonyl fluoride bits (SuFBits), available for screening against protein targets. SuFBits will label the target if it binds to the core fragment, which facilitates the identification of weak fragments by mass spectrometry. LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Chiovini, Balázs AU - Müller, Dalma AU - Tóth, Estilla Zsófia AU - Fülöp, Anna AU - Ábrányi-Balogh, Péter AU - Wittner, Lucia AU - Várady, György AU - Farkas, Ödön AU - Turczel, Gábor AU - Katona, Gergely AU - Győrffy, Balázs AU - Keserű, György Miklós AU - Mucsi, Zoltán AU - Rózsa J., Balázs AU - Kovács, Ervin TI - Synthesis and Application of Two-Photon Active Fluorescent Rhodol Dyes for Antibody Conjugation and In Vitro Cell Imaging JF - ACS OMEGA J2 - ACS OMEGA VL - 8 PY - 2023 IS - 25 SP - 22836 EP - 22843 PG - 8 SN - 2470-1343 DO - 10.1021/acsomega.3c01796 UR - https://m2.mtmt.hu/api/publication/34015800 ID - 34015800 N1 - Funding Agency and Grant Number: National Office of Science, Innovation and Technology (NKFIH) [2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, 2020-1.1.5-GYORSITOSAV-2021-00004, TKP2021-NVA-14]; New National Excellence Program of the Ministry for Innovation and Technology [NKFIH PD124598, BO/799/21/7]; Janos Bolyai Research Scholarship [UNKP-22-ME3] Funding text: The research was supported by the 2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, 2020-1.1.5-GYORSITOSAV-2021-00004, and TKP2021-NVA-14 grants of the National Office of Science, Innovation and Technology (NKFIH). We are grateful for the support of NKFIH PD124598 and UNKP-19-3-I-BME-408 New National Excellence Program of the Ministry for Innovation and Technology and Janos Bolyai Research Scholarship (BO/799/21/7, UNKP-22-ME3). The authors acknowledge the supportive work of Krisztina Nemeth. We are grateful for the possibility to use ELKH Cloud, which helped us achieve the results published in this paper. LA - English DB - MTMT ER - TY - JOUR AU - Szepesi Kovács, Dénes AU - Kontra, Bence AU - Chiovini, Balázs AU - Müller, Dalma AU - Tóth, Estilla Zsófia AU - Ábrányi-Balogh, Péter AU - Wittner, Lucia AU - Várady, György AU - Turczel, Gábor AU - Farkas, Ödön AU - Owen, Michael Christopher AU - Katona, Gergely AU - Győrffy, Balázs AU - Keserű, György Miklós AU - Mucsi, Zoltán AU - Rózsa J., Balázs AU - Kovács, Ervin TI - Effective Synthesis, Development and Application of a Highly Fluorescent Cyanine Dye for Antibody Conjugation and Microscopy Imaging JF - ORGANIC & BIOMOLECULAR CHEMISTRY J2 - ORG BIOMOL CHEM VL - 21 PY - 2023 IS - 44 SP - 8829 EP - 8836 PG - 8 SN - 1477-0520 DO - 10.1039/D3OB01471A UR - https://m2.mtmt.hu/api/publication/34205650 ID - 34205650 N1 - Funding Agency and Grant Number: National Office of Science, Innovation and Technology (NKFIH) [2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, TKP2021-NVA-15, 2020-1.1.5-GYORSITOSAV-2021-00004, 2020-2.1.1-ED-2021-00190, 2020-2.1.1-ED-2022-00208, TKP2021-NVA-14]; Janos Bolyai Research Scholarship [BO/799/21/7, UNKP-22-ME3] Funding text: This research was supported by the 2018-1.3.1-VKE-2018-00032, KFI-18-2018-00097, TKP2021-EGA-42, TKP2021-NVA-15, 2020-1.1.5-GYORSITOSAV-2021-00004, 2020-2.1.1-ED-2021-00190, 2020-2.1.1-ED-2022-00208 and TKP2021-NVA-14 grants of the National Office of Science, Innovation and Technology (NKFIH). We are grateful for the support from the Janos Bolyai Research Scholarship (BO/799/21/7, UNKP-22-ME3). The authors acknowledge the supportive work of Krisztina Nemeth. On behalf of the Development and mechanistic study of DNA dyes (PI: Dr Ervin Kovacs, ELKH Research Centre for Natural Sciences) project we are grateful for the possibility to use ELKH Cloud,53 which helped us achieve the results published in this paper. AB - An asymmetric cyanine-type fluorescent dye was designed and synthesized via a versatile, multi-step process, aiming to conjugate with an Her2+ receptor specific antibody by an azide-alkyne click reaction. The aromaticity and the excitation and relaxation energetics of the fluorophore were characterized by computational methods. The synthesized dye exhibited excellent fluorescence properties for confocal microscopy, offering efficient applicability in in vitro imaging due to its merits such as a high molar absorption coefficient (36 816 M-1 cm-1), excellent brightness, optimal wavelength (627 nm), larger Stokes shift (26 nm) and appropriate photostability compared to cyanines. The conjugated cyanine-trastuzumab was constructed via an effective, metal-free, strain-promoted azide-alkyne click reaction leading to a regulated number of dyes being conjugated. This novel cyanine-labelled antibody was successfully applied for in vitro confocal imaging and flow cytometry of Her2+ tumor cells. An azido cyanine dye was synthesized and characterized by computational and experimental techniques and applied in tumor cell imaging. LA - English DB - MTMT ER -