Plasmodium dipeptidyl aminopeptidases as malaria transmission-blocking drug targets

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