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: Takeshi Q Tanaka, Edgar Deu, Alvaro Molina-Cruz, Michael J Ashburne, Omar Ali, Amreena Suri, Sandhya Kortagere, Matthew Bogyo, Kim C Williamson
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 10 Pg. 4645-52 (Oct 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23836185 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antimalarials
• Aminopeptidases

Topics

• Aminopeptidases (antagonists & inhibitors, genetics, metabolism)
• Animals
• Antimalarials (pharmacology)
• Female
• Male
• Mice
• Plasmodium falciparum (drug effects, enzymology, genetics)
• Reverse Transcriptase Polymerase Chain Reaction