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

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.

Graphical Abstract

Keywords:

• COVID-19
• antivirals
• iminosugars
• host-directed action
• pandemic preparedness
• glycosidase inhibitors

Acknowledgments:

This research was supported by the Science Fund of the Republic of Serbia, within the Special Research Program COVID-19, Project No: 7547552, Acronym: SMART Repurposing.

Author contributions statement

Zorana Ferjancic: investigation, project administration, methodology. Filip Bihelovic: investigation, project administration, methodology. Bojan Vulovic: investigation, methodology, visualisation. Radomir Matovic: investigation. Milena Trmcic: investigation, writing – review and editing. Aleksandar Jankovic: investigation. Milos Pavlovic: investigation. Filip Djurkovic: investigation. Radivoje Prodanovic: methodology, supervision, formal analysis. Aleksandra Djurdjevic Djelmas: investigation, formal analysis. Nevena Kalicanin: investigation, formal analysis. Mario Zlatovic: investigation, methodology, software, formal analysis, visualisation, data curation. Dusan Sladic: methodology, conceptualisation, supervision, formal analysis, validation, writing – original draft, writing – review & editing. Thomas Vallet: investigation, formal analysis, visualisation, methodology. Marco Vignuzzi: supervision, methodology, resources, writing – editing & review. Radomir N. Saicic: conceptualisation, funding acquisition, project administration, methodology, supervision, validation, writing – original draft, writing – editing and review.

Declaration of interest statement

The authors report there are no competing interests to declare.