@article{MTMT:35295180, title = {In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors}, url = {https://m2.mtmt.hu/api/publication/35295180}, author = {Maluck, Sara and Bobrovsky, Rivka and Poór, Miklós and Lange, Roman W. and Steinmetzer, Torsten and Jerzsele, Ákos and Adorján, András and Bajusz, Dávid and Rácz, Anita and Pászti-Gere, Erzsébet}, doi = {10.3390/biomedicines12092075}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {12}, unique-id = {35295180}, abstract = {Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α1-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4.}, year = {2024}, eissn = {2227-9059}, pages = {2075}, orcid-numbers = {Poór, Miklós/0000-0003-1425-7459; Lange, Roman W./0009-0004-7752-6403; Steinmetzer, Torsten/0000-0001-6523-4754; Jerzsele, Ákos/0000-0002-3380-0827; Adorján, András/0000-0002-2555-6123; Bajusz, Dávid/0000-0003-4277-9481} } @article{MTMT:35265081, title = {Progress on the development of Class A GPCR‐biased ligands}, url = {https://m2.mtmt.hu/api/publication/35265081}, author = {Morales, Paula and Scharf, Magdalena M. and Bermudez, Marcel and Egyed, Attila and Franco, Rafael and Hansen, Olivia K. and Jagerovic, Nadine and Jakubík, Jan and Keserű, György Miklós and Kiss, Dóra Judit and Kozielewicz, Pawel and Larsen, Olav and Majellaro, Maria and Mallo‐Abreu, Ana and Navarro, Gemma and Prieto‐Díaz, Rubén and Rosenkilde, Mette M. and Sotelo, Eddy and Stark, Holger and Werner, Tobias and Wingler, Laura M.}, doi = {10.1111/bph.17301}, journal-iso = {BR J PHARMACOL}, journal = {BRITISH JOURNAL OF PHARMACOLOGY}, unique-id = {35265081}, issn = {0007-1188}, abstract = {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.}, year = {2024}, eissn = {1476-5381}, orcid-numbers = {Scharf, Magdalena M./0000-0002-3305-3956; Bermudez, Marcel/0000-0002-7421-3282; Franco, Rafael/0000-0003-2549-4919; Jakubík, Jan/0000-0002-1737-1487; Kozielewicz, Pawel/0000-0003-1414-3566; Navarro, Gemma/0000-0003-4654-0873; Rosenkilde, Mette M./0000-0001-9600-3254; Stark, Holger/0000-0003-3336-1710} } @article{MTMT:35262191, title = {Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives}, url = {https://m2.mtmt.hu/api/publication/35262191}, author = {Horváth, Dániel and Stráner, Pál and Taricska, Nóra and Fazekas, Zsolt and Karancsiné Menyhárd, Dóra and Perczel, András}, doi = {10.1021/acs.jmedchem.4c01553}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, unique-id = {35262191}, issn = {0022-2623}, year = {2024}, eissn = {1520-4804}, orcid-numbers = {Horváth, Dániel/0000-0001-8239-3933; Stráner, Pál/0000-0003-2240-8501; Taricska, Nóra/0000-0002-9721-953X; Fazekas, Zsolt/0000-0001-5007-4807; Karancsiné Menyhárd, Dóra/0000-0002-0095-5531; Perczel, András/0000-0003-1252-6416} } @CONFERENCE{MTMT:35201379, title = {Anizol és Mezitilén platformkémia összehasonlító vizsgálata}, url = {https://m2.mtmt.hu/api/publication/35201379}, author = {Nemeskéri, Dániel}, booktitle = {Új Nemzeti Kiválóság Program intézményi záró konferencia ELTE - Absztraktkötet}, unique-id = {35201379}, year = {2024}, pages = {44-44} } @article{MTMT:35196297, title = {The PARP inhibitor rucaparib blocks SARS-CoV-2 virus binding to cells and the immune reaction in models of COVID-19}, url = {https://m2.mtmt.hu/api/publication/35196297}, author = {Papp, H. and Tóth, Emese and Bóvári-Biri, J. and Bánfai, K. and Juhász, P. and Mahdi, M. and Russo, L.C. and Bajusz, Dávid and Sipos, Adrienn and Petri, László and Szalai, Tibor Viktor and Kemény, Ágnes and Madai, M. and Kuczmog, A. and Batta, Gyula and Mózner, Orsolya and Vaskó, Dorottya and Hirsch, Edit and Bohus, P. and Méhes, G. and Tőzsér, J. and Curtin, N.J. and Helyes, Zsuzsanna and Tóth, A. and Hoch, N.C. and Jakab, F. and Keserű, György Miklós and Pongrácz, J.E. and Bay, Péter}, doi = {10.1111/bph.17305}, journal-iso = {BR J PHARMACOL}, journal = {BRITISH JOURNAL OF PHARMACOLOGY}, unique-id = {35196297}, issn = {0007-1188}, abstract = {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.}, keywords = {NFκB; rucaparib; ACE2; COVID-19; SARS-CoV-2 spike protein; SARS-CoV-2 RNA; viral lung inflammation}, year = {2024}, eissn = {1476-5381}, orcid-numbers = {Bajusz, Dávid/0000-0003-4277-9481; Kemény, Ágnes/0000-0002-4523-3938; Batta, Gyula/0000-0002-0442-1828; Mózner, Orsolya/0000-0001-5784-7702; Vaskó, Dorottya/0000-0002-2502-0644} } @article{MTMT:35176724, title = {Site-Selective Antibody Conjugation with Dibromopyrazines.}, url = {https://m2.mtmt.hu/api/publication/35176724}, author = {Szepesi Kovács, Dénes and Pásztor, Bettina and Ábrányi-Balogh, Péter and Petri, László and Imre, Tímea and Simon, József and Tátrai, Enikő and Várady, György and Tóvári, József and Szijj, Peter A and Keserű, György Miklós}, doi = {10.1021/acs.bioconjchem.4c00296}, journal-iso = {BIOCONJUGATE CHEM}, journal = {BIOCONJUGATE CHEMISTRY}, volume = {Aug 16}, unique-id = {35176724}, issn = {1043-1802}, abstract = {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.}, year = {2024}, eissn = {1520-4812}, orcid-numbers = {Tátrai, Enikő/0000-0001-9778-2077; Tóvári, József/0000-0002-5543-3204} } @{MTMT:35161458, title = {Cyclic designer scaffolds for the covalent targeting of proteins via michael addition}, url = {https://m2.mtmt.hu/api/publication/35161458}, author = {Reményi, Attila and Soós, Tibor and Póti, Ádám Levente and Bálint, Dániel and Alexa, Anita and Sok, Péter Dániel and Torda, Lili and Varga, Szilárd and Ozsváth, Kristóf and Albert, Krisztián and Palkó, Roberta and Ember, Orsolya and Kállainé Szarka, Eszter and Imre, Timea}, unique-id = {35161458}, abstract = {Many biologically active natural products contain electrophilic Michael acceptor fragments. For example, curcumin and 4-hydroxyderricin contain an acyclic α,β-unsaturated ketone that alkylates cysteines. Other antitumor or anti-inflammatory herbal compounds such as Withaferin A or zerumbone contain cyclic α,β-unsaturated ketones and react with nucleophilic residues of proteins. These observations contributed to a paradigm shift in drug design and development in the last two decades: various drugs with covalent warhead have been developed and approved. Despite the apparent importance and success of covalent warheads in current drug design and developments, the applied warheads display a rather limited structural variance and complexity which automatically limits the attainable chemical space. Furthermore, to minimize possible side-reactions during the synthesis of drugs, the applied warheads are added appendages in the late-stage of the synthetic route, thus a warhead scaffold that can be synthetically easily varied using orthogonal chemistry and used as a tunable covalent warhead is still missing. Such a structurally more complex scaffold would be much more like the warheads of the natural products and is expected to be more selective in targeting nucleophiles found on the proteins. Moreover, owing to a larger contact surface, it might be more suitable for targeting shallow protein surfaces involved in protein-protein interactions.}, year = {2024}, orcid-numbers = {Varga, Szilárd/0000-0001-9611-5168} } @{MTMT:35161423, title = {SYNTHESIS OF α,β-UNSATURATED CARBONYLS FROM ALKENES VIA SULFONIUM INTERMEDIATES AND THEIR APPLICATION IN THE SYNTHESIS OF CONJUGATED DIENE PHEROMONES, KAIROMONES, AND RELATED COMPOUNDS}, url = {https://m2.mtmt.hu/api/publication/35161423}, author = {Angyal, Péter and Kotschy, András Miklós and Dudás, Ádám and Soós, Tibor and Varga, Szilárd}, unique-id = {35161423}, abstract = {α,β-Unsaturated aldehydes are useful products as such in agrochemistry, but also potential intermediates for the preparation of important insect pheromones and kairomones. Until now, primarily the thermodynamically more stable (E)-α,β-unsaturated aldehydes have been identified as useful intermediates in the production of conjugated diene pheromone compounds, however, their practical and cost-effective synthesis on an industrial scale remains challenging. The problem to be solved by the present invention is to provide a method for selective oxidation of alkenes to α,β-unsaturated carbonyls which can be further transformed into pheromones and kairomones preferably without isolation and significant loss of the existing stereochemical purity.}, year = {2024}, orcid-numbers = {Dudás, Ádám/0000-0002-6841-8185; Varga, Szilárd/0000-0001-9611-5168} } @article{MTMT:35160281, title = {Mapping protein binding sites by photoreactive fragment pharmacophores}, url = {https://m2.mtmt.hu/api/publication/35160281}, author = {Ábrányi-Balogh, Péter and Bajusz, Dávid and Orgován, Zoltán and Keeley, Aaron Brian and Petri, László and Péczka, Nikolett and Szalai, Tibor Viktor and Pálfy, Gyula and Gadanecz, Márton and Grant, Emma K. and Imre, Tímea and Takács, Tamás and Randelovic, Ivan and Baranyi, Marcell and Marton, András Dénes and Schlosser, Gitta (Vácziné) and Ashraf, Qirat F. and de Araujo, Elvin D. and Karancsi, Tamás and Buday, László and Tóvári, József and Perczel, András and Bush, Jacob T. and Keserű, György Miklós}, doi = {10.1038/s42004-024-01252-w}, journal-iso = {COMMUN CHEM}, journal = {COMMUNICATIONS CHEMISTRY}, volume = {7}, unique-id = {35160281}, issn = {2399-3669}, abstract = {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.}, year = {2024}, eissn = {2399-3669}, orcid-numbers = {Bajusz, Dávid/0000-0003-4277-9481; Pálfy, Gyula/0000-0003-1590-5331; Gadanecz, Márton/0009-0009-8076-7597; Grant, Emma K./0009-0005-5229-9125; Randelovic, Ivan/0000-0003-0161-0022; Schlosser, Gitta (Vácziné)/0000-0002-7637-7133; de Araujo, Elvin D./0000-0003-0716-2830; Tóvári, József/0000-0002-5543-3204; Perczel, András/0000-0003-1252-6416; Bush, Jacob T./0000-0001-7165-0092} } @article{MTMT:35145349, title = {PK/PD investigation of antiviral host matriptase/TMPRSS2 inhibitors in cell models}, url = {https://m2.mtmt.hu/api/publication/35145349}, author = {Gamba, Dávid and van Eijk, Nicholas and Lányi, Katalin and Monostory, Katalin and Steinmetzer, Torsten and Marosi, András and Rácz, Anita and Bajusz, Dávid and Kruhl, Diana and Böttcher-Friebertshäuser, Eva and Pásztiné Gere, Erzsébet}, doi = {10.1038/s41598-024-67633-2}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {14}, unique-id = {35145349}, issn = {2045-2322}, abstract = {Certain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets for the treatment of viral respiratory infections. In this study, the cytotoxicity and inhibitory effects of seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, and MI-1904) on cytochrome P450 enzymes were evaluated using fluorometric assays. Additionally, their antiviral activity against influenza A virus subtypes H1N1 and H9N2 was assessed. The metabolic depletion rates of these inhibitors in human primary hepatocytes were determined over a 120-min period by LC–MS/MS, and PK parameters were calculated. The tested compounds, with the exception of MI-21, displayed potent inhibition of CYP3A4, while all compounds lacked inhibitory effects on CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The differences between the CYP3A4 activity within the series were rationalized by ligand docking. Elucidation of PK parameters showed that inhibitors MI-463, MI-472, MI-485, MI-1900 and MI-1904 were more stable compounds than MI-21 and MI-1903. Anti-H1N1 properties of inhibitors MI-463 and MI-1900 and anti-H9N2 effects of MI-463 were shown at 20 and 50 µM after 24 h incubation with the inhibitors, suggesting that these inhibitors can be applied to block entry of these viruses by suppressing host matriptase/TMPRSS2-mediated cleavage.}, year = {2024}, eissn = {2045-2322}, orcid-numbers = {Lányi, Katalin/0000-0003-1992-6324; Bajusz, Dávid/0000-0003-4277-9481} }