# Licochalcone A as a Potential Anti-Toxoplasma Agent: A Target Identification and Pharmacokinetic Study

## TL;DR

Licochalcone A, a natural compound, shows promise as a new treatment for toxoplasmosis by targeting specific proteins and crossing the blood-brain barrier.

## Contribution

The study identifies TgMORN1 as a key target of Licochalcone A and demonstrates its pharmacokinetic potential for treating brain infections.

## Key findings

- Licochalcone A binds to TgMORN1, a key protein in Toxoplasma, reducing parasite proliferation.
- Licochalcone A crosses the blood-brain barrier and inhibits brain cyst formation in Toxoplasma.
- Pharmacokinetic analysis shows Licochalcone A has favorable absorption and brain permeability.

## Abstract

Toxoplasmosis is a zoonotic disease with limited therapeutic options, which are further hampered by significant toxicity and suboptimal efficacy. Effective interventions for chronic infection remain insufficient, and thus, natural product-derived drug screening remains a key focus in anti-Toxoplasma research. Licochalcone A (Lico A), a major bioactive compound isolated from Glycyrrhiza uralensis, exhibits potent activity against Toxoplasma tachyzoites. However, systematic studies of its targets, pharmacokinetics, and efficacy are lacking, hindering its development as an anti-Toxoplasma candidate drug. In this study, we used SPR-MS to identify 33 high-affinity target proteins (affinity score > 1000). Furthermore, an AI-driven multidimensional analysis identified a cluster of five proteins (TgMORN1, D3XD37, ABCB2, MIC15, and IDH), with TgMORN1 yielding the highest composite score. RNAi experiments confirmed TgMORN1 as a key target, as its silencing attenuated the anti-proliferative effect of Lico A. Western blotting, NanoDSF, and SPR supported direct binding between Lico A and TgMORN1, suggesting that Lico A modulates TgMORN1 thermal stability through residues S168 and D203, with high species specificity. Pharmacokinetic evaluation revealed that Lico A had favorable absorption and blood–brain barrier permeability, supporting its potential utility in treating brain disease. In vitro assays showed that Lico A effectively inhibited Toxoplasma gondii brain cyst formation. Collectively, these findings support Lico A as a promising candidate for the treatment of toxoplasmosis.