title: Plasmodium dipeptidyl aminopeptidases as malaria transmission-blocking drug targets.
abstract: The Plasmodium falciparum and P. berghei genomes each contain three dipeptidyl aminopeptidase (dpap) homologs. dpap1 and -3 are critical for asexual growth, but the role of dpap2, the gametocyte-specific homolog, has not been tested. If DPAPs are essential for transmission as well as asexual growth, then a DPAP inhibitor could be used for treatment and to block transmission. To directly analyze the role of DPAP2, a dpap2-minus P. berghei (Pbdpap2Δ) line was generated. The Pbdpap2Δ parasites grew normally, differentiated into gametocytes, and generated sporozoites that were infectious to mice when fed to a mosquito. However, Pbdpap1 transcription was >2-fold upregulated in the Pbdpap2Δ clonal lines, possibly compensating for the loss of Pbdpap2. The role of DPAP1 and -3 in the dpap2Δ parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to the Pbdpap2Δ parasites just before a mosquito membrane feed, mosquito infectivity was not affected. To assess longer exposures to ML4118S and further evaluate the role of DPAPs during gametocyte development in a parasite that causes human malaria, the dpap2 deletion was repeated in P. falciparum. Viable P. falciparum dpap2 (Pfdpap2)-minus parasites were obtained that produced morphologically normal gametocytes. Both wild-type and Pfdpap2-negative parasites were sensitive to ML4118S, indicating that, unlike many antimalarials, ML4118S has activity against parasites at both the asexual and sexual stages and that DPAP1 and -3 may be targets for a dual-stage drug that can treat patients and block malaria transmission.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Takeshi Q
authors.initials: TQ
authors.lastname: Tanaka
authors.forename: Edgar
authors.initials: E
authors.lastname: Deu
authors.forename: Alvaro
authors.initials: A
authors.lastname: Molina-Cruz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ashburne
authors.forename: Omar
authors.initials: O
authors.lastname: Ali
authors.forename: Amreena
authors.initials: A
authors.lastname: Suri
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kortagere
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.forename: Kim C
authors.initials: KC
authors.lastname: Williamson
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000962:Antimalarials; D000626:Aminopeptidases