Thymoquinone for COVID-19

Abstract: Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the recent pandemic and worldwide outbreak of respiratory disease. Since there are no known specific drugs for fighting this virus and the process for new drug development is lengthy, scientists have been trying to develop drugs against this viral infection. The potent antiviral activity of natural products has been confirmed in several previous studies. Viral and host proteins contributing to COVID-19 infections can be targeted by natural compounds derived from plants, marine organisms, and microorganisms. The most important of these compounds are polyphenols (e.g., anthraquinone polyphenol, hinokinin, curcumin, and epigallocatechin gallate), alkaloids (e.g., isoquinoline, 10- hydroxyusambarensine, anisotine, and adhatodine), and terpenoids (salvinorin A, thymoquinone, bilobalide, ginkgolide A, and celastrol) from plants, sulphated polysaccharides (carrageenans, chondroitin sulfate C, and fucoidan) from marine organisms, and glycocin F and lactococcin G phycocyanin, and lipopeptide from microorganisms. This study reviews these compounds and their mechanism of action for treating COVID-19 infection and guides researchers in developing effective and safe therapeutic agents against this disease from naturally derived compounds.

Since the emergence of the pandemic of the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the discovery of antiviral phytoconstituents from medicinal plants against SARS-CoV-2 has been comprehensively researched. In this study, thirty-three plants belonging to seventeen different families used traditionally in Saudi Arabia were tested in vitro for their ability to inhibit the SARS-CoV-2 main protease (MPRO). Major constituents of the bio-active extracts were isolated and tested for their inhibition potential against this enzyme; in addition, their antiviral activity against the SARS-CoV-2 Egyptian strain was assessed. Further, the thermodynamic stability of the best active compounds was studied through focused comparative insights for the active metabolites regarding ligand–target binding characteristics at the molecular level. Additionally, the obtained computational findings provided useful directions for future drug optimization and development. The results revealed that Psiadia punctulata, Aframomum melegueta, and Nigella sativa extracts showed a high percentage of inhibition of 66.4, 58.7, and 31.5%, against SARS-CoV-2 MPRO, respectively. The major isolated constituents of these plants were identified as gardenins A and B (from P. punctulata), 6-gingerol and 6-paradol (from A. melegueta), and thymoquinone (from N. sativa). These compounds are the first to be tested invitro against SARS-CoV-2 MPRO. Among the isolated compounds, only thymoquinone (THY), gardenin A (GDA), 6-gingerol (GNG), and 6-paradol (PAD) inhibited the SARS-CoV-2 MPRO enzyme with inhibition percentages of 63.21, 73.80, 65.2, and 71.8%, respectively. In vitro assessment of SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020 (accession number on GSAID: EPI_ISL_430820) revealed a strong-to-low antiviral activity of the isolated compounds. THY showed relatively high cytotoxicity and was anti-SARS-CoV-2, while PAD demonstrated a cytotoxic effect on the tested VERO cells with a selectivity index of CC50/IC50 = 1.33 and CC50/IC50 = 0.6, respectively. Moreover, GNG had moderate activity at non-cytotoxic concentrations in vitro with a selectivity index of CC50/IC50 = 101.3/43.45 = 2.3. Meanwhile, GDA showed weak activity with a selectivity index of CC50/IC50 = 246.5/83.77 = 2.9. The thermodynamic stability of top-active compounds revealed preferential stability and SARS-CoV-2 MPRO binding affinity for PAD through molecular-docking-coupled molecular dynamics simulation. The obtained results suggest the treating potential of these plants and/or their active metabolites for COVID-19. However, further in-vivo and clinical investigations are required to establish the potential preventive and treatment effectiveness of these plants and/or their bio-active compounds in COVID-19.