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Journal article
Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets
Antimicrobial agents and chemotherapy, v 57(10), pp 4645-4652
13 Sep 2013
PMID: 23836185
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets
- Creators
- Takeshi Q Tanaka - National Institute of Allergy and Infectious DiseasesEdgar Deu - Stanford MedicineAlvaro Molina-Cruz - National Institute of Allergy and Infectious DiseasesMichael J Ashburne - Loyola University ChicagoOmar Ali - Loyola University ChicagoAmreena Suri - Loyola University ChicagoSandhya Kortagere - Drexel UniversityMatthew Bogyo - Stanford MedicineKim C Williamson - Loyola University Chicago
- Publication Details
- Antimicrobial agents and chemotherapy, v 57(10), pp 4645-4652
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000324480300007
- Scopus ID
- 2-s2.0-84884251262
- Other Identifier
- 991019167939504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy