Symptomatic Protective Action of Glycyrrhizin (Licorice) in COVID-19 Infection?

Abstract

The role of the ACE2 enzyme in the COVID-19 infection is 2-fold, with opposing implications for the disease development. 1. The membrane bound angiotensin converting enzyme 2 (ACE2) serves as the entry point of COVID-19 2. Conversely, it supports an anti-inflammatory pathway. This led to the controversy of the impact of medications, which influence its expression. ACE2 is part of the wider renin-angiotensin-aldosterone system (RAAS) and is upregulated via compounds, which inhibits the classical ACE, thereby plasma aldosterone and aldosterone receptor (MR) activation. MR activation may therefore protect organs from binding the COVID-19 by reducing ACE2 expression. Glycyrrhizin (GL) is a frequent component in traditional Chinese medicines, which have been used to control COVID-19 infections. Its systemically active metabolite glycyrrhetinic acid (GA) inhibits 11beta hydroxysteroid dehydrogenase(11betaHSD2) and activates MR in organs, which express this enzyme, including the lungs. Does this affect the protective effect of ACE2? Importantly, GL has anti-inflammatory properties by itself via toll like receptor 4 (TLR4) antagonism and therefore compensates for the reduced protection of the downregulated ACE2. Finally, a direct effect of GL or GA to reduce virus transmission exists, which may involve reduced expression of type 2 transmembrane serine protease (TMPRSS2), which is required for virus uptake. Glycyrrhizin may reduce the severity of an infection with COVID-19 at the two stages of the COVID-19 induced disease process, 1. To block the number of entry points and 2. provide an ACE2 independent anti-inflammatory mechanism.

Keywords: 11 beta hydroxysteroid dehydrogenase; COVID-19; Corona virus; angiotensin converrting enzyme; glycyrrhizin; inflammation; mineralocorticoid receptor; toll like receptor 4 (TLR4).

Figure 1

Schematic model of the effect of glycyrrhizin: COVID-19 access into cells is mediated via ACE2 with TMPRSS2 as a co-factor. The expression of ACE2 is regulated by mineralocorticoid receptors (MR): MR activation leads to a reduction of ACE2 expression; GA inhibits the 11βHSD2, which allows cortisol to activate MR, followed by ACE2-downregulation (arrow 1). TMPRSS2 sensitizes ACE2 for the update of the virus into the cell. GA leads to a reduced expression of TMPRSS2 and may therefore provide an additional mechanism to restrict the virus' access into the cell (arrow 2). ACE2 has an anti-inflammatory mechanism by the generation of angiotensin 1-7 and angiotensin 1-9. Via activation of MAS or angiotensin 2 receptors inflammatory pathways are suppressed. This also includes a reduced expression and/or activation of the membrane TLR4 receptor (left), i.e., the reduced ACE2 expression could be regarded as problematic (35). However, GA directly inhibits TLR4 independent of ACE2 activation (Arrow 3). (ϕ and interrupted lines symbolize inhibition; red continuous lines symbolize activation).