Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies
Аутори
Ferjančić, ZoranaBihelović, Filip
Vulović, Bojan
Matović, Radomir
Trmčić, Milena
Jankovic, Aleksandar
Pavlovic, Milos
Đurković, Filip T.
Prodanović, Radivoje
Djurdjevic Djelmas, Aleksandra
Kalicanin, Nevena
Zlatović, Mario
Sladić, Dušan
Vallet, Thomas
Vignuzzi, Marco
Saicic, Radomir N.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential... drug candidates for other viral infections.
Кључне речи:
antivirals / COVID-19 / glycosidase inhibitors / host-directed action / iminosugars / pandemic preparednessИзвор:
Journal of Enzyme Inhibition and Medicinal Chemistry, 2024, 39, 1, 2289007-Издавач:
- Taylor and Francis Group
Финансирање / пројекти:
- SMART Repurposing – Small Molecule Anti-RNA-virus Therapy. Repurposing Iminosugars and Chloroquine Analogues Against COVID-19 (RS-ScienceFundRS-Fond_2020_COVID19-7547552)
Институција/група
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Ferjančić, Zorana AU - Bihelović, Filip AU - Vulović, Bojan AU - Matović, Radomir AU - Trmčić, Milena AU - Jankovic, Aleksandar AU - Pavlovic, Milos AU - Đurković, Filip T. AU - Prodanović, Radivoje AU - Djurdjevic Djelmas, Aleksandra AU - Kalicanin, Nevena AU - Zlatović, Mario AU - Sladić, Dušan AU - Vallet, Thomas AU - Vignuzzi, Marco AU - Saicic, Radomir N. PY - 2024 UR - http://cherry.chem.bg.ac.rs/handle/123456789/6475 AB - We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections. PB - Taylor and Francis Group T2 - Journal of Enzyme Inhibition and Medicinal Chemistry T1 - Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies VL - 39 IS - 1 SP - 2289007 DO - 10.1080/14756366.2023.2289007 ER -
@article{ author = "Ferjančić, Zorana and Bihelović, Filip and Vulović, Bojan and Matović, Radomir and Trmčić, Milena and Jankovic, Aleksandar and Pavlovic, Milos and Đurković, Filip T. and Prodanović, Radivoje and Djurdjevic Djelmas, Aleksandra and Kalicanin, Nevena and Zlatović, Mario and Sladić, Dušan and Vallet, Thomas and Vignuzzi, Marco and Saicic, Radomir N.", year = "2024", abstract = "We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.", publisher = "Taylor and Francis Group", journal = "Journal of Enzyme Inhibition and Medicinal Chemistry", title = "Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies", volume = "39", number = "1", pages = "2289007", doi = "10.1080/14756366.2023.2289007" }
Ferjančić, Z., Bihelović, F., Vulović, B., Matović, R., Trmčić, M., Jankovic, A., Pavlovic, M., Đurković, F. T., Prodanović, R., Djurdjevic Djelmas, A., Kalicanin, N., Zlatović, M., Sladić, D., Vallet, T., Vignuzzi, M.,& Saicic, R. N.. (2024). Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies. in Journal of Enzyme Inhibition and Medicinal Chemistry Taylor and Francis Group., 39(1), 2289007. https://doi.org/10.1080/14756366.2023.2289007
Ferjančić Z, Bihelović F, Vulović B, Matović R, Trmčić M, Jankovic A, Pavlovic M, Đurković FT, Prodanović R, Djurdjevic Djelmas A, Kalicanin N, Zlatović M, Sladić D, Vallet T, Vignuzzi M, Saicic RN. Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies. in Journal of Enzyme Inhibition and Medicinal Chemistry. 2024;39(1):2289007. doi:10.1080/14756366.2023.2289007 .
Ferjančić, Zorana, Bihelović, Filip, Vulović, Bojan, Matović, Radomir, Trmčić, Milena, Jankovic, Aleksandar, Pavlovic, Milos, Đurković, Filip T., Prodanović, Radivoje, Djurdjevic Djelmas, Aleksandra, Kalicanin, Nevena, Zlatović, Mario, Sladić, Dušan, Vallet, Thomas, Vignuzzi, Marco, Saicic, Radomir N., "Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies" in Journal of Enzyme Inhibition and Medicinal Chemistry, 39, no. 1 (2024):2289007, https://doi.org/10.1080/14756366.2023.2289007 . .