Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission
dc.contributor.author | Gomez-Gonzalez, Paula-Josefina | |
dc.contributor.author | Gupta, Antima | |
dc.contributor.author | Drought, Laura G. | |
dc.contributor.author | Patel, Avnish | |
dc.contributor.author | Okombo, John | |
dc.contributor.author | Van der Watt, Mariette Elizabeth | |
dc.contributor.author | Walker-Gray, Ryan | |
dc.contributor.author | Schindler, Kyra A. | |
dc.contributor.author | Burkhard, Anna Y. | |
dc.contributor.author | Yeo, Tomas | |
dc.contributor.author | Narwal, Sunil K. | |
dc.contributor.author | Bloxham, Talia S. | |
dc.contributor.author | Flueck, Christian | |
dc.contributor.author | Walker, Eloise M. | |
dc.contributor.author | Rey, Joshua A. | |
dc.contributor.author | Fairhurst, Kate J. | |
dc.contributor.author | Reader, Janette | |
dc.contributor.author | Park, Heekuk | |
dc.contributor.author | Pollard, Harry G. | |
dc.contributor.author | Stewart, Lindsay B. | |
dc.contributor.author | Brandner-Garrod, Luke | |
dc.contributor.author | Kristan, Mojca | |
dc.contributor.author | Sterk, Geert-Jan | |
dc.contributor.author | Van Nuland, Youri M. | |
dc.contributor.author | Manko, Emilia | |
dc.contributor.author | Van Schalkwyk, Donelly A. | |
dc.contributor.author | Zheng, Yang | |
dc.contributor.author | Leurs, Rob | |
dc.contributor.author | Dechering, Koen J. | |
dc.contributor.author | Aguiar, Anna Caroline C. | |
dc.contributor.author | Guido, Rafael V.C. | |
dc.contributor.author | Pereira, Dhelio B. | |
dc.contributor.author | Tumwebaze, Patrick K. | |
dc.contributor.author | Nosbya, Samuel L. | |
dc.contributor.author | Rosenthal, Philip J. | |
dc.contributor.author | Cooper, Roland A. | |
dc.contributor.author | Palmer, Mike | |
dc.contributor.author | Parkinson, Tanya | |
dc.contributor.author | Burrows, Jeremy N. | |
dc.contributor.author | Uhlemann, Anne-Catrin | |
dc.contributor.author | Birkholtz, Lyn-Marie | |
dc.contributor.author | Small-Saunders, Jennifer L. | |
dc.contributor.author | Duffy, James | |
dc.contributor.author | Fidock, David A. | |
dc.contributor.author | Brown, Alan | |
dc.contributor.author | Gardner, Mark | |
dc.contributor.author | Baker, David A. | |
dc.date.accessioned | 2025-07-02T07:40:33Z | |
dc.date.available | 2025-07-02T07:40:33Z | |
dc.date.issued | 2024-10-06 | |
dc.description | DATA AND MATERIALS AVAILABILITY : All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. | |
dc.description.abstract | Cyclic nucleotide–dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent Plasmodium falciparum PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates. Two of the inhibitor subseries also have potent transmission-blocking activity by targeting PDEs expressed during sexual parasite development. In vitro drug selection experiments generated parasites with moderately reduced susceptibility to the inhibitors. Whole-genome sequencing of these parasites detected no mutations in PDEβ but rather mutations in downstream effectors: either the catalytic or regulatory subunits of cyclic adenosine monophosphate–dependent protein kinase (PKA) or in the 3-phosphoinositide-dependent protein kinase that is required for PKA activation. Several properties of these P. falciparum PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline. | |
dc.description.department | Biochemistry, Genetics and Microbiology (BGM) | |
dc.description.department | UP Centre for Sustainable Malaria Control (UP CSMC) | |
dc.description.librarian | am2025 | |
dc.description.sdg | SDG-03: Good health and well-being | |
dc.description.sdg | SDG-02: Zero Hunger | |
dc.description.sponsorship | The Wellcome Trust for Innovator and Investigator Awards; the Biomedical Resources Grant; resistance selection studies and research on Ugandan parasites were supported in part by the US National Institutes of Health and the Bill & Melinda Gates Foundation; the Medicines for Malaria Venture. | |
dc.description.uri | https://www.science.org/journal/sciadv | |
dc.identifier.citation | Gomez-Gonzalez, P.-J., Gupta, A., Drought, L.G. et al. 2024, 'Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission', Science Advances, vol. 10, pp. 1-19. DOI: 10.1126/sciadv.adq1383. | |
dc.identifier.issn | 2375-2548 | |
dc.identifier.other | 10.1126/sciadv.adq1383 | |
dc.identifier.uri | http://hdl.handle.net/2263/103101 | |
dc.language.iso | en | |
dc.publisher | American Association for the Advancement of Science | |
dc.rights | © 2024 The Authors. Distributed under a creative commons Attribution license 4.0 (cc BY). | |
dc.subject | Inhibitors | |
dc.subject | Malaria | |
dc.subject | Phosphodiesterases (PDEs) | |
dc.subject | Antimalarial drug targets | |
dc.title | Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission | |
dc.type | Article |
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