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.

• Authors: N Mehyar, A Mashhour, I Islam, H A Alhadrami, A M Tolah, B Alghanem, S Alkhaldi, B A Somaie, M Al Ghobain, Y Alobaida, A S Alaskar, M Boudjelal
• Journal: SAR and QSAR in environmental research (SAR QSAR Environ Res) Vol. 32 Issue 12 Pg. 963-983 (Dec 2021) ISSN: 1029-046X [Electronic] England
• PMID: 34818959 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Indoles
• Phenylcarbamates
• Sulfonamides
• DNA Helicases
• zafirlukast

Topics

• Animals
• Antiviral Agents (pharmacology)
• Chlorocebus aethiops
• DNA Helicases (antagonists & inhibitors)
• Fluorescence Resonance Energy Transfer
• Indoles (pharmacology)
• Phenylcarbamates (pharmacology)
• Quantitative Structure-Activity Relationship
• SARS-CoV-2 (drug effects, enzymology)
• Sulfonamides (pharmacology)
• Vero Cells
• Virus Replication (drug effects)
• COVID-19 Drug Treatment