Tanaka, Takeshi Q.; Deu, Edgar; Molina-Cruz, Alvaro; Ashburne, Michael J.; Ali, Omar; Suri, Amreena; Kortagere, Sandhya; Bogyo, Matthew; Williamsona, Kim C.
Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 57:4645-4652, OCT 2013

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 (Pbdpap2 Delta) line was generated. The Pbdpap2 Delta 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 Pbdpap2 Delta clonal lines, possibly compensating for the loss of Pbdpap2. The role of DPAP1 and -3 in the dpap2 Delta parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to the Pbdpap2 Delta 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.

DOI:10.1128/AAC.02495-12

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