Inhibitors of Toxoplasma Autophagy-related Peptidases as an Anti-parasitic Strategy

Toxoplasma gondii is a pathogen that is able to infect virtually all species of warm-blooded animals. In humans, this parasite is responsible for a potentially serious disease called toxoplasmosis. This pathology affects immuno-compromised patients and, in the congenital form of the disease, the parasite can also be transmitted from the mother to her foetus through the placenta. T. gondii replicates in the tissues of the contaminated host, where it causes significant damage. We have strong evidences that a cellular process called autophagy is important for the intracellular replication of the parasite. Autophagy is a process that involves degradation of unnecessary or dysfunctional cellular components through the lysosomal machinery. Interfering with the function of autophagy-related protease TgATG4 in T. gondii leads to a growth arrest of the parasites. We are now seeking to develop specific inhibitors of this enzyme to block parasite replication. In addition, parasitic lysosomal proteases are likely to be involved in the later parts of the autophagic process and can also be screened in order to identify additional inhibitors of parasite development. This collaborative project is between a Stanford University team specialized in the design of therapeutic protease inhibitors and a French laboratory studying the molecular bases of the autophagic function in Toxoplasma.