Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?

Abstract

Safe and efficient drugs to combat the current COVID-19 pandemic are urgently needed. In this context, we have analyzed the anti-coronavirus potential of the natural product glycyrrhizic acid (GLR), a drug used to treat liver diseases (including viral hepatitis) and specific cutaneous inflammation (such as atopic dermatitis) in some countries. The properties of GLR and its primary active metabolite glycyrrhetinic acid are presented and discussed. GLR has shown activities against different viruses, including SARS-associated Human and animal coronaviruses. GLR is a non-hemolytic saponin and a potent immuno-active anti-inflammatory agent which displays both cytoplasmic and membrane effects. At the membrane level, GLR induces cholesterol-dependent disorganization of lipid rafts which are important for the entry of coronavirus into cells. At the intracellular and circulating levels, GLR can trap the high mobility group box 1 protein and thus blocks the alarmin functions of HMGB1. We used molecular docking to characterize further and discuss both the cholesterol- and HMG box-binding functions of GLR. The membrane and cytoplasmic effects of GLR, coupled with its long-established medical use as a relatively safe drug, make GLR a good candidate to be tested against the SARS-CoV-2 coronavirus, alone and in combination with other drugs. The rational supporting combinations with (hydroxy)chloroquine and tenofovir (two drugs active against SARS-CoV-2) is also discussed. Based on this analysis, we conclude that GLR should be further considered and rapidly evaluated for the treatment of patients with COVID-19.

Keywords: COVID-19; Cholesterol; Coronavirus; Glycyrrhizin; HMGB1; Natural product.

Fig. 1

(a) Structures of glycyrrhizic acid (GLR) and glycyrrhetinic acid (GA). GLR is composed of a central saponin core flanked by a carbohydrate side chain at C-3. Below, the molecular models of GLR and GA show the accessible surface and hydrophilic (purple) and lipophilic (green) sites. For GLR, the central triterpenoid aglycone, largely hydrophobic, is bound to a hydrophilic sugar chain. The model of GA (aglycone) is shown for comparison. Models were built with Discovery Studio 2020 Client, Dassault Systemes Biovia Corp..

Fig. 2

Antiviral activities of GLR. The drug is active against aa number of viruses in vitro. In vivo activities have been reported with a few viruses, notably HIV-1. But the main antiviral activity is against the hepatitis viruses A, B and C. The drug is used in Human to treat liver diseases, notably chronic viral hepatitis.

Fig. 3

Illustration of the self-assembling of GLR to form a fibrillar network. Molecules of GLR associate in an anti-parallel orientation, with stacking of the hydrophobic sapogenin moieties to form fibrils. Depending on the conditions, GLR can also for micelles and other structures which can be used to entrap other small molecules, as a drug delivery system. The entrapment of molecules into a fibrillar network is illustrated.

Fig. 4

The fibrillar self-assembly of GLR. (a) Confocal laser scanning microscopy image of an emulsion gel stabilized by 4 wt% GLR nanofibrils (Thioflavin T fluorescence highlights GLR the fibrillar network). (b) 0.2 wt% GLR nanofibrils observed by atomic force microscopy. (c) 0.1 wt% GLR nanofibrils observed by transmission electron microscopy. (d) Scanning electron microscopy image of the aqueous phase network of an emulsion gel stabilized by 4 wt% GLR nanofibrils. (images kindly provided by Prof. Xiao-Quan Yang, Dpt of Food Science and Technology, South China University of Technology, Guangzhou, China).

Fig. 5

Molecular models of the interaction between GLR (purple) and cholesterol (green). The two different orientations show the stacking of the two hydrophobic parts of each molecule and the contacts made with the glycoside moiety of GLR which contribute to clamp the cholesterol unit.

Fig. 6

Global view of the complexes formed between GLR (top) or GA (bottom) with the HMG box motif of the B domain of HMG1 (PDB code: 1HME). The procedure used to construct the models is described Table 2.

Fig. 7

Views of the GLR- and GA-HMG complexes with a focus on the H-bond and hydrophobic surfaces exposed implicated in the protein complex formation. Note the specific contribution of the carbohydrate moiety of GLR to the protein interaction. In both cases, the specific color code is indicated.

Fig. 8

Binding map contacts for GLR and GA bound to the HMG box.

Fig. 9

Chemical structures of two saponins (platycodin D and saikosaponin A), and two drugs that could be combined with GLR (chloroquine and tenofovir), mentioned in this study.

Fig. 10

Summary of the main characteristics and properties of GLR, supporting its potential activity against the SARS-CoV-2 coronavirus. The drug is safe, used for a long time to treat viral hepatitis (iv and oral formulations available). GLR binds to cholesterol, thereby affecting the organization of lipid rafts that are essential for the entry of the virus into cells. GLR forms stable complexes with HMGB1 protein, thereby blocking the propagation of the danger signals. GLR displays antiviral activities against multiple viruses, including hepatitis virus A-B-C and some coronavirus.