title: Cysteine protease inhibitors block Toxoplasma gondii microneme secretion and cell invasion.
abstract: Toxoplasma gondii enters host cells via an active, self-driven process to fulfill its need for intracellular replication and survival. Successful host cell invasion is governed by sequential release of secretory proteins from three specialized organelles, including the micronemes, which contribute adhesive proteins necessary for parasite attachment and penetration. Cumulative evidence from studies of Trypanosoma species and malaria parasites has shown that cysteine protease inhibitors represent potent anti-parasitic agents capable of curing infections in vivo. In this study, we screened a series of selective cysteine protease inhibitors for their effects on T. gondii cell invasion. Two of these compounds, morpholinourea-leucyl-homophenolalaninyl-phenyl-vinyl-sulfone and N-benzoxycarbonyl-(leucyl)3-phenyl-vinyl-sulfone, impaired T. gondii invasion and gliding motility at low-micromolar concentrations. Unexpectedly, these inhibitors did not affect surface proteolysis of microneme products but instead impaired an earlier step by precluding the secretion of microneme-derived adhesins to the parasite surface. Our findings suggest that cysteine protease activity is required for microneme secretion and cell invasion by T. gondii.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Chin Fen
authors.initials: CF
authors.lastname: Teo
authors.forename: Xing Wang
authors.initials: XW
authors.lastname: Zhou
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.forename: Vern B
authors.initials: VB
authors.lastname: Carruthers
mesh_terms: D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006790:Host-Parasite Interactions / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects* / Q000378:metabolism; D014123:Toxoplasmosis / Q000188:drug therapy / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D013450:Sulfones