Mechanism of action of glycyrrhizin against <i>Plasmodium falciparum</i>

Extracts of the plant Glycyrrhiza glabra (licorice) are used in traditional medicine to treat malaria. The main active components are the saponin glycyrrhizin (GLR) and its active metabolite glycyrrhetinic acid (GA) which both display activities against Plasmodium falciparum. We have identified three main mechanisms at the origin of their anti-plasmodial activity: (i) drug-induced disorganisation of membrane lipid rafts, (ii) blockade of the alarmin protein HMGB1 and (iii) potential inhibition of the detoxifying enzyme glyoxalase 1 (GLO-1) considered as an important drug target for malaria. Our analysis shed light on the mechanism of action of GLR against P. falciparum.

Key words:
cholesterol; glycyrrhizin; glyoxalase 1; HMGB1; Malaria; Plasmodium

Authorship

Maria de Nazaré Correia Soeiro

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Biologia Celular, Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz-FiocruzBrazilRio de Janeiro, RJ, BrazilFundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Biologia Celular, Rio de Janeiro, RJ, Brasil

Gérard Vergoten

University of Lille, Inserm, Institut de Chimie Pharmaceutique Albert Lespagnol, Faculté de Pharmacie, Lille, FranceUniversity of LilleFranceLille, FranceUniversity of Lille, Inserm, Institut de Chimie Pharmaceutique Albert Lespagnol, Faculté de Pharmacie, Lille, France

Christian Bailly ⁺+ Corresponding author: christian.bailly@oncowitan.com

OncoWitan, Lille, FranceOncoWitanFranceLille, FranceOncoWitan, Lille, France

http://orcid.org/0000-0002-2973-9357

+ Corresponding author: christian.bailly@oncowitan.com

CBA conducted the review and drafted an initial version of the manuscript; GV performed the molecular modeling analysis; MNCS completed and finalised the manuscript. The authors declare that there are no conflicts of interest related to the content of this article.

SCIMAGO INSTITUTIONS RANKINGS

OncoWitan, Lille, FranceOncoWitanFranceLille, FranceOncoWitan, Lille, France

Figures | Tables

Figures (5)
Tables (1)

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Fig. 1:
structures of glycyrrhizin (GLR) and its plasma metabolites 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid (MGA) and glycyrrhetinic acid (GA). The parent product bearing a disaccharide is converted into the monosaccharide MGA and the aglycone GA under the action of β-glucuronidases (βG).

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Fig. 2:
molecular models of the interaction between the indicated compound (green) and cholesterol (blue). Complexes are stabilised by stacking interactions between the hydrophobic part of each molecule and with glycyrrhizin (GLR) and 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid (MGA), additional contacts implicating the glycoside moiety contribute to clamp the cholesterol unit. In each case, the computed potential energy of interaction (ΔE) is indicated.

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Fig. 3:
molecular models of the interaction of glycyrrhizin (GLR), 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid (MGA) and glycyrrhetinic acid (GA) with HMG1 from Plasmodium falciparum (PDB code: 2MRC). The procedure used to construct the models is described Table. In all cases, the drugs correspond to the 18α-epimers. The protein surface is shown in green (A) or a ribbon model in red (B) to illustrate the three helices. (C) Binding map contacts are shown, with the indicated colour code.

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Fig. 4:
inhibition of Glyoxalase-1 by 18β-glycyrrhetinic acid (18β-GA), an enzyme implicated in the metabolism of toxic methylglyoxal converted into non-toxic D-lactate by the glyoxalase system.

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Fig. 5:
proposed anti-malaria mechanism of action of glycyrrhizin (GLR). The saponin drug disorganises the plasma membrane and cholesterol-rich lipid rafts, in part through the trapping of cholesterol, thus perturbing the cell entry of the parasite and its metabolism. In addition, GLR can block the activity of both Plasmodium falciparum HMGB1 (PfHMGB1) and Human HMGB1 (HsHMGB1), thus exerting an anti-inflammatory action and blocking HMGB1-related damage-associated molecular pattern molecule (DAMP) signals. Additionally, the potential inhibition of parasite glyoxalase-1 by GLR can be considered.

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TABLE
Calculated potential energy of interaction (ΔE) and free energy of hydration (ΔG) of the drug-HMGB1 complexes^a

Fig. 1: structures of glycyrrhizin (GLR) and its plasma metabolites 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid (MGA) and glycyrrhetinic acid (GA). The parent product bearing a disaccharide is converted into the monosaccharide MGA and the aglycone GA under the action of β-glucuronidases (βG).

Fig. 2: molecular models of the interaction between the indicated compound (green) and cholesterol (blue). Complexes are stabilised by stacking interactions between the hydrophobic part of each molecule and with glycyrrhizin (GLR) and 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid (MGA), additional contacts implicating the glycoside moiety contribute to clamp the cholesterol unit. In each case, the computed potential energy of interaction (ΔE) is indicated.

Fig. 3: molecular models of the interaction of glycyrrhizin (GLR), 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid (MGA) and glycyrrhetinic acid (GA) with HMG1 from Plasmodium falciparum (PDB code: 2MRC). The procedure used to construct the models is described Table. In all cases, the drugs correspond to the 18α-epimers. The protein surface is shown in green (A) or a ribbon model in red (B) to illustrate the three helices. (C) Binding map contacts are shown, with the indicated colour code.

Fig. 4: inhibition of Glyoxalase-1 by 18β-glycyrrhetinic acid (18β-GA), an enzyme implicated in the metabolism of toxic methylglyoxal converted into non-toxic D-lactate by the glyoxalase system.

Fig. 5: proposed anti-malaria mechanism of action of glycyrrhizin (GLR). The saponin drug disorganises the plasma membrane and cholesterol-rich lipid rafts, in part through the trapping of cholesterol, thus perturbing the cell entry of the parasite and its metabolism. In addition, GLR can block the activity of both Plasmodium falciparum HMGB1 (PfHMGB1) and Human HMGB1 (HsHMGB1), thus exerting an anti-inflammatory action and blocking HMGB1-related damage-associated molecular pattern molecule (DAMP) signals. Additionally, the potential inhibition of parasite glyoxalase-1 by GLR can be considered.

TABLE Calculated potential energy of interaction (ΔE) and free energy of hydration (ΔG) of the drug-HMGB1 complexes^a

	Pf HMGB1^b		Hs HMGB1 (Box-B)^b
Cpds	ΔE (kcal/mol)	ΔG (kcal/mol)	ΔE (kcal/mol)	ΔG (kcal/mol)
GLR	-96.57	-32.70	-83.66	-21.65
MGA	-79.73	-29.50	-72.86	-18.55
GA	-46.35	-25.0	-32.32	-18.84

a: the 3D structure of HMG proteins was retrieved from the Protein Data Bank (www.rcsb.org) under the PDB codes 1HME (HMG box motif in the B domain of HMG1) and 2MRC (NMR Structure for High mobility group protein from Plasmodium falciparum 3D7). Docking experiments were performed as previously described;⁽²⁴⁾ b: HMGB1 from P. falciparum and Box-B of Human HMGB1. Cpds: compounds; GA: glycyrrhetinic acid; GLR: glycyrrhizin; MGA: 3-O-mono-β-D-glucuronyl-glycyrrhetinic acid.

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Mechanism of action of glycyrrhizin against <i>Plasmodium falciparum</i>

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[1] + Corresponding author: christian.bailly@oncowitan.com