Thomas Mouveaux1, Dante Rotili2, Tom Boissavy1, Emmanuel Roger1, Christine Pierrot1, Antonello Mai2, Mathieu Gissot3. 1. Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France. 2. Dipartimento di Chimica e Tecnologie del Farmaco "Sapienza" Università di Roma, 00185, Rome, Italy. 3. Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France. Electronic address: mathieu.gissot@pasteur-lille.fr.
Abstract
INTRODUCTION: Toxoplasmosis is a major health issue worldwide, especially for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii. Although the drugs commonly used to treat toxoplasmosis are efficient, they present serious side effects and adverse events are common. Therefore, there is a need for the discovery of new compounds with potent anti-Toxoplasma gondii activity. METHODS: This study tested compounds designed to target enzymes that are involved in the epigenetic regulation of gene expression. RESULTS: Among the most active compounds, an HDAC inhibitor showing an IC50 of 30 nM with a selectivity index above 100 was identified. MC1742 was active at inhibiting the growth of the parasite in vitro but also at preventing the consequences of the acute disease in vivo. This compound induced hyper-acetylation of histones, while the acetylated tubulin level remained unchanged. After MC1742 treatment, the parasite expression profile was profoundly changed with the activation of genes preferentially expressed in the sexual stages that are normally repressed in the tachyzoite stage. CONCLUSIONS: These findings suggest that this compound disturbs the Toxoplasma gondii gene expression program, inducing parasite death.
INTRODUCTION: Toxoplasmosis is a major health issue worldwide, especially for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii. Although the drugs commonly used to treat toxoplasmosis are efficient, they present serious side effects and adverse events are common. Therefore, there is a need for the discovery of new compounds with potent anti-Toxoplasma gondii activity. METHODS: This study tested compounds designed to target enzymes that are involved in the epigenetic regulation of gene expression. RESULTS: Among the most active compounds, an HDAC inhibitor showing an IC50 of 30 nM with a selectivity index above 100 was identified. MC1742 was active at inhibiting the growth of the parasite in vitro but also at preventing the consequences of the acute disease in vivo. This compound induced hyper-acetylation of histones, while the acetylated tubulin level remained unchanged. After MC1742 treatment, the parasite expression profile was profoundly changed with the activation of genes preferentially expressed in the sexual stages that are normally repressed in the tachyzoite stage. CONCLUSIONS: These findings suggest that this compound disturbs the Toxoplasma gondii gene expression program, inducing parasite death.