Discovery of Zafirlukast as a novel SARS-CoV-2 helicase inhibitor using in silico modelling and a FRET-based assay

ABSTRACT

The coronavirus helicase is an essential enzyme required for viral replication/transcription pathways. Structural studies revealed a sulphate moiety that interacts with key residues within the nucleotide-binding site of the helicase. Compounds with a sulphoxide or a sulphone moiety could interfere with these interactions and consequently inhibit the enzyme. The molecular operating environment (MOE) was used to dock 189 sulphoxide and sulphone-containing FDA-approved compounds to the nucleotide-binding site. Zafirlukast, a leukotriene receptor antagonist used to treat chronic asthma, achieved the lowest docking score at −8.75 kcals/mol. The inhibitory effect of the compounds on the SARS-CoV-2 helicase dsDNA unwinding activity was tested by a FRET-based assay. Zafirlukast was the only compound to inhibit the enzyme (IC50 = 16.3 µM). The treatment of Vero E6 cells with 25 µM zafirlukast prior to SARS-CoV-2 infection decreased the cytopathic effects of SARS-CoV-2 significantly. These results suggest that zafirlukast alleviates SARS-CoV-2 pathogenicity by inhibiting the viral helicase and impairing the viral replication/transcription pathway. Zafirlukast could be clinically developed as a new antiviral treatment for SARS-CoV-2 and other coronavirus diseases. This discovery is based on molecular modelling, in vitro inhibition of the SARS-CoV helicase activity and cell-based SARS-CoV-2 viral replication.

KEYWORDS:

• COVID-19
• Sars-Cov-2
• helicase
• marketed drugs
• repurposing
• zafirlukast

Acknowledgements

We thank KAIMRC for funding this research. We thank all KAIMRC researchers and administrative staff for assisting directly and indirectly in this research.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

All the data used to support the findings of this study are included in the article, and supplementary information is provided in the supplementary section. In addition, the data used to support the findings of this study are available from the corresponding author on request.

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1993995

Additional information

Funding

This research work has been funded by the King Abdullah International Medical Research Center, KAIMRC (projects RC15/163 and RC20/219).