Inhibition of malaria parasite development by a cyclic peptide that targets the vital parasite protein SERA5.
The serine repeat antigen (SERA) proteins of the malaria parasites Plasmodium spp. contain a putative enzyme domain similar to that of papain family cysteine proteases. In Plasmodium falciparum parasites, more than half of the SERA family proteins, 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 noncanonical 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 characterization of the interaction shows that 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 that of 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 in 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 accumulates within the parasitophorous vacuole. In addition, both SBP1 and SERA5 were identified in the parasite cytosol, indicating that the plasma membrane of the parasite was compromised as a result of SBP1 treatment. These data implicate an important role for SERA5 in the regulation of the intraerythrocytic development of late-stage parasites and as a target for drug development.
Fairlie
W Douglas
WD
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Spurck
Tim P
TP
McCoubrie
Joanne E
JE
Gilson
Paul R
PR
Miller
Susanne K
SK
McFadden
Geoffrey I
GI
Malby
Robyn
R
Crabb
Brendan S
BS
Hodder
Anthony N
AN
D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism*; D000962:Antimalarials / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011485:Protein Binding; D014617:Vacuoles / Q000737:chemistry / Q000469:parasitology
D000953:Antigens, Protozoan; D000962:Antimalarials; D019151:Peptide Library; D010456:Peptides, Cyclic; C480167:serine repeat antigen 5, Plasmodium falciparum; D003546:Cysteine Endopeptidases