Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies

Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies

Journal of Enzyme Inhibition and Medicinal Chemistry

10.1080/14756366.2023.2289007

https://doi.org/10.1080/14756366.2023.2289007

Zorana Ferjancic, Filip Bihelovic, Bojan Vulovic, Radomir Matovic, Milena Trmcic, Aleksandar Jankovic, Milos Pavlovic, Filip Djurkovic, Radivoje Prodanovic, Aleksandra Djurdjevic Djelmas, Nevena Kalicanin, Mario Zlatovic, Dusan Sladic, Thomas Vallet, Marco Vignuzzi, Radomir N. Saicic

13 December 2023

Ferjancic, Z., Bihelovic, F., Vulovic, B., Matovic, R., Trmcic, M., Jankovic, A., Pavlovic, M., Djurkovic, F., Prodanovic, R., Djurdjevic Djelmas, A., Kalicanin, N., Zlatovic, M., Sladic, D., Vallet, T., Vignuzzi, M., Saicic, R. N. (2023). Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 39(1). https://doi.org/10.1080/14756366.2023.2289007

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.

Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

There was no specific funding for the research done

Copyright 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent

https://oar.a-star.edu.sg/communities-collections/articles/22609

1475-6366
1475-6374

A*STAR Infectious Disease Labs

https://doi.org/10.1080/14756366.2023.2289007