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Stage-Specific and Selective Delivery of Caged Azidosugars into the Intracellular Parasite Toxoplasma gondii by Using an Esterase-Ester Pair Technique

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Selective delivery of small molecules into intracellular parasites is particularly problematic due to the presence of multiple membranes and surrounding host cells. We have devised a method that can deliver… Click to show full abstract

Selective delivery of small molecules into intracellular parasites is particularly problematic due to the presence of multiple membranes and surrounding host cells. We have devised a method that can deliver caged molecules into an intracellular parasite, Toxoplasma gondii, that express an uncaging enzyme in a stage-specific manner without affecting host cell biology. This system provides a valuable tool for studying many intracellular parasites. ABSTRACT Toxoplasma gondii is an obligate intracellular parasite that chronically infects up to a third of the human population. The parasites persist in the form of cysts in the central nervous system and serve as a reservoir for the reactivation of toxoplasmic encephalitis. The cyst wall is known to have abundant O-linked N-acetylgalactosamine glycans, but the existing metabolic labeling methods do not allow selective labeling of intracellular parasite glycoproteins without labeling of host glycans. In this study, we have integrated Cu(I)-catalyzed bioorthogonal click chemistry with a specific esterase-ester pair system in order to selectively deliver azidosugars to the intracellular parasites. We demonstrated that α-cyclopropyl modified GalNAz was cleaved by porcine liver esterase produced in the parasites but not in the host cells. Our proof-of-concept study demonstrates the feasibility and potential of this esterase-ester click chemistry approach for the selective delivery of small molecules in a stage-specific manner. IMPORTANCE Selective delivery of small molecules into intracellular parasites is particularly problematic due to the presence of multiple membranes and surrounding host cells. We have devised a method that can deliver caged molecules into an intracellular parasite, Toxoplasma gondii, that express an uncaging enzyme in a stage-specific manner without affecting host cell biology. This system provides a valuable tool for studying many intracellular parasites.

Keywords: toxoplasma gondii; selective delivery; intracellular parasite; stage specific; host

Journal Title: mSphere
Year Published: 2019

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