The evaluation of traditionally used medicinal plants against targets associated with COVID-19

Abstract

Covid-19 infection is characterized by multiple stages of symptoms, from mild flu-like symptoms to pneumonia and potential death. The sudden nature of the pandemic warranted immediate treatment and the repurposing of existing drugs was prioritized. Multiple vaccines are approved by the Food and Drug Administration (FDA) to limit the infection rate but there is still a need for the targeted treatment of Covid-19. This study evaluated selected medicinal plants based on their traditional use and the available literature on their ethnopharmacology. Ethanolic extracts of the samples were tested for activity against specific targets associated with Covid-19. The number of samples was filtered down to provide lead candidates for future research. Many of the extracts tested on human lung fibroblast (MRC-5) cells in the current study have not been tested on the cell line before. Of the selected plants, Aspalathus linearis, Bulbine frutescens, Clausena anisata, Capparis tomentosa, Foeniculum vulgare, Myrsine africana, Podocarpus latifolius, Polygala virgata, Rhoicissus tridentata and Tylosema esculentum reported no toxicity (IC50 > 400 μg/ml). Factor Xa plays an important role in blood coagulation through the process of activating prothrombin to thrombin. Foeniculum. vulgare, M. africana, P. latifolius and R. tridentata exhibited varying anticoagulant activity. Both R. tridentata (139.10 ± 4.70 μg/ml) and P. latifolius (193.45 ± 10.35 μg/ml) showed the greatest anticoagulant potential. This is the first report of both M. africana and R. tridentata being studied for their FXa inhibitory activity. Cytochrome P450 enzymes are essential in the metabolism of many important drugs. The potential herb-drug interactions were tested F. vulgare, M. africana, P. latifolius and R. tridentata against CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6 and CYP3A4. Myrsine africana showed increased activity in all CYP P450 enzymes tested when compared to the 100 % 14 activity control. Foeniculum vulgare and R. tridentata showed increased activity of CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. Furthermore, P. latifolius increased the activity of CYP 1A2, CYP 2D6 and CYP 3A4 activity but notably inhibited CYP 2C19 and CYP 2C9. Covid-19 infection causes an inflammatory response known as cytokine release syndrome. When tested against human inflammatory cytokines, F. vulgare and M. africana decreased IL- 6 expression (48 % and 24 % respectively) at 100 μg/ml, although at 200 μg/ml, M. africana showed a 77% increase in IL-6 expression. Furthermore, F. vulgare and M. africana inhibited the expression of IL-8 by 36% and 64% respectively (100 μg/ml) and 27 % and 36 % respectively at 200 μg/ml. Podocarpus latifolius showed inhibition of IL- 12p70 (22 %), IL-6 (66 %) and IL-8 (77 %) at 100 μg/ml and increased expression of IL-12p70 (24 %), TNF-α (98 %), IL-6 (113 %) and IL- 8 (78 %) at 200 μg/ml. Rhoicissus tridentata exhibited 12 % inhibition of IL- 6 at 100 μg/ml while inhibiting IL-8 expression (47 % at 100 μg/ml and 51% at 200 μg/ml) and increasing the expression of IL- 6 (23 %) and TNF-α (120 %) at 200 μg/ml. After evaluation of the selected extracts against targets associated with Covid-19 infection, four lead candidates displayed potential for further investigation. The chosen extracts exhibited good activity on different targets in this study suggesting further assessment into combination studies and the possible identification of bioactive compounds. Treatment targeted specifically at Covid-19 is still needed. This study explores the possibility for a plant derived product to fill this gap and provides the initial steps towards further research targeted towards this goal. This current study is the first report of both FXa inhibition and anti-inflammatory studies against pro-inflammatory cytokines in M. africana and R. tridentata.