Cysteine protease inhibitors block invasion

Antimicrob Agents Chemother. 2006 Dec 4; [Epub ahead of print]

Cysteine Protease Inhibitors Block Toxoplasma Microneme Secretion and Cell Invasion.

Teo CF, Zhou XW, Boygo M, Carruthers VB.

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore MD 21205; Department of Pathology, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305.

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 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, LHVS and ZL3VS 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.PMID: 17145790 [PubMed - as supplied by publisher]