ABSTRACT
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 SARS-CoV-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 SARS-CoV-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 SARS-CoV-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.
Subject(s)
Antiviral Agents/pharmacology , Ergosterol/metabolism , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Virus Replication/drug effects , Vitamin D/pharmacology , Antiviral Agents/chemistry , Ergosterol/analogs & derivatives , Ergosterol/chemistry , Ergosterol/pharmacology , Molecular Docking Simulation , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/physiology , Vitamin D/chemistryABSTRACT
(1) Background: Vitamin D, a well-established regulator of calcium and phosphate metabolism, also has immune-modulatory functions. An uncontrolled immune response and cytokine storm are tightly linked to fatal courses of COVID-19. The present retrospective study aimed to inves-tigate vitamin D status markers and vitamin D degradation products in a mixed cohort of 148 hospitalized COVID-19 patients with various clinical courses of COVID-19. (2) Methods: The serum concentrations of 25(OH)D3, 25(OH)D2, 24,25(OH)2D3, and 25,26(OH)2D3 were determined by a validated liquid-chromatography tandem mass-spectrometry method in leftover serum samples from 148 COVID-19 patients that were admitted to the University Hospital of the Medical Uni-versity of Graz between April and November 2020. Anthropometric and clinical data, as well as outcomes were obtained from the laboratory and hospital information systems. (3) Results: From the 148 patients, 34 (23%) died within 30 days after admission. The frequency of fatal outcomes did not differ between males and females. Non-survivors were significantly older than survivors, had higher peak concentrations of IL-6 and CRP, and required mechanical ventilation more frequently. The serum concentrations of all vitamin D metabolites and the vitamin D metabolite ratio (VMR) did not differ significantly between survivors and non-survivors. Additionally, the need for res-piratory support was unrelated to the serum concentrations of 25(OH)D vitamin D and the two vitamin D catabolites, as well as the VMR. (4) Conclusion: The present results do not support a relevant role of vitamin D for the course and outcome of COVID-19.