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Infect. Immun. doi:10.1128/IAI.00278-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inhibition of malaria parasite development by a cyclic peptide that targets the vital parasite protein, SERA5

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia; The School of Botany, The University of Melbourne, Grattan St, Parkville, Victoria 3010, Australia

^* To whom correspondence should be addressed. Email: hodder{at}wehi.edu.au.

	Abstract

The serine repeat antigen (SERA) proteins of the malaria parasite Plasmodium spp. contain a putative enzyme domain similar to Papain family cysteine proteases. In P. falciparum parasites, more than half of the SERA family including the most abundantly expressed form, SERA5, have a cysteine to serine substitution within the putative catalytic triad of the active site. Although SERA5 is required for blood-stage parasite survival, the occurrence of a non-canonical catalytic triad casts doubt on the importance of the enzyme domain in this function. We used phage display to identify a small (14 residue) disulfide-bonded, cyclic peptide (SBP1) that targets the enzyme domain of SERA5. Biochemical characterisation of the interaction shows it is dependent on the conformation of both the peptide and protein. Addition of this peptide to parasite cultures compromised development of late-stage parasites compared to control parasites or those incubated with equivalent amounts of the carboxymethylated peptide. This effect was similar in two different strains of P. falciparum, as well as a transgenic strain where the gene encoding the related ‘serine-type’ parasitophorous vacuole protein, SERA4, was deleted. In compromised parasites, the SBP1 peptide crosses both the erythrocyte and parasitophorous vacuole membranes and accumulate within the parasitophorous vacuole. In addition, both SBP1 and SERA5 were identified in the parasite cytosol indicating the plasma membrane of the parasite wascompromised as a result of SBP1 treatment. This data implicates an important role for SERA5 in the regulation of the intra-erythrocytic development of late-stage parasites, and as a target for drug development.