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Discovery of Zafirlukast as a novel SARS-CoV-2 helicase inhibitor using in silico modelling and a FRET-based assay.
Mehyar, N; Mashhour, A; Islam, I; Alhadrami, H A; Tolah, A M; Alghanem, B; Alkhaldi, S; Somaie, B A; Al Ghobain, M; Alobaida, Y; Alaskar, A S; Boudjelal, M.
  • Mehyar N; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
  • Mashhour A; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
  • Islam I; King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
  • Alhadrami HA; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
  • Tolah AM; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
  • Alghanem B; King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
  • Alkhaldi S; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
  • Somaie BA; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
  • Al Ghobain M; King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
  • Alobaida Y; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Rabigh, Saudi Arabia.
  • Alaskar AS; Molecular Diagnostic Laboratory, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia.
  • Boudjelal M; Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
SAR QSAR Environ Res ; 32(12): 963-983, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1532255
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Sulfonamides / DNA Helicases / Phenylcarbamates / SARS-CoV-2 / Indoles Type of study: Prognostic study Limits: Animals Language: English Journal: SAR QSAR Environ Res Journal subject: Environmental Health Year: 2021 Document Type: Article Affiliation country: 1062936x.2021.1993995

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Sulfonamides / DNA Helicases / Phenylcarbamates / SARS-CoV-2 / Indoles Type of study: Prognostic study Limits: Animals Language: English Journal: SAR QSAR Environ Res Journal subject: Environmental Health Year: 2021 Document Type: Article Affiliation country: 1062936x.2021.1993995