期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 321, 期 2, 页码 E246-E251出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00174.2021
关键词
COVID-19; lumisterol; RNA-dependent RNA polymerase; SARS-CoV-2 main protease; vitamin D metabolites
资金
- National Institutes of Health [1R01AR073004-01A1, R01AR071189-01A1]
- Veteran Administration merit Grants [1I01BX004293-01A1, R21 AI149267-01A1]
- Indian Council of Medical Research Grant [ISRM/12(22)/2020]
The study found that metabolites of vitamin D and lumisterol can inhibit key enzymes in the SARS-CoV-2 replication machinery, suggesting a novel potential for antiviral drug research.
Vitamin D deficiency significantly correlates with the severity of SARS-CoV-2 infection. Molecular docking-based virtual screening studies predict that novel vitamin D and related lumisterol hydroxymetabolites are able to bind to the active sites of two SARSCoV-2 transcription machinery enzymes with high affinity. These enzymes are the main protease (Mpro) and RNA-dependent RNA polymerase (RdRP), which play important roles in viral replication and establishing infection. Based on predicted binding affinities and specific interactions, we identified 10 vitamin D3 (D3) and lumisterol (L3) analogs as likely binding partners of SARSCoV-2 Mpro and RdRP and, therefore, tested their ability to inhibit these enzymes. Activity measurements demonstrated that 25 (OH)L3, 24(OH)L3, and 20(OH)7DHC are the most effective of the hydroxymetabolites tested at inhibiting the activity of SARSCoV-2 Mpro causing 10%-19% inhibition. These same derivatives as well as other hydroxylumisterols and hydroxyvitamin D3 metabolites inhibited RdRP by 50%-60%. Thus, inhibition of these enzymes by vitamin D and lumisterol metabolites may provide a novel approach to hindering the SARS-CoV-2 infection. NEW & NOTEWORTHY Active forms of vitamin D and lumisterol can inhibit SARS-CoV-2 replication machinery enzymes, which indicates that novel vitamin D and lumisterol metabolites are candidates for antiviral drug research.
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