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Gomez-Gonzalez, Paula-Josefina, Gupta, Antima, Drought, Laura G, Patel, Avnish, Okombo, John, van der Watt, Mariëtte, Walker-Gray, Ryan, Schindler, Kyra A, Burkhard, Anna Y, Yeo, Tomas, Narwal, Sunil K, Bloxham, Talia S, Flueck, Christian, Walker, Eloise M, Rey, Joshua A, Fairhurst, Kate J, Reader, Janette, Park, Heekuk, Pollard, Harry G, Stewart, Lindsay B, Brandner-Garrod, Luke, Kristan, Mojca, Sterk, Geert-Jan, van Nuland, Youri M, Manko, Emilia, van Schalkwyk, Donelly A, Zheng, Yang, Leurs, Rob, Dechering, Koen J, Aguiar, Anna Caroline C, Guido, Rafael V C, Pereira, Dhelio B, Tumwebaze, Patrick K, Nosbya, Samuel L, Rosenthal, Philip J, Cooper, Roland A, Palmer, Mike, Parkinson, Tanya, Burrows, Jeremy, Uhlemann, Anne-Catrin, Birkholtz, Lyn-Marié, Small-Saunders, Jennifer L, Duffy, James, Fidock, David A, Brown, Alan, Gardner, Mark and Baker, David A (2024) 'Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.'. Science Advances, Vol 10, Issue 49, eadq1383.
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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.
| Item Type: | Article |
|---|---|
| Subjects: | QX Parasitology > QX 45 Host-parasite relations QX Parasitology > Insects. Other Parasites > QX 510 Mosquitoes WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria |
| Faculty: Department: | Biological Sciences > Department of Tropical Disease Biology |
| Digital Object Identifer (DOI): | https://doi.org/10.1126/sciadv.adq1383 |
| Related URLs: | |
| SWORD Depositor: | JISC Pubrouter |
| Depositing User: | JISC Pubrouter |
| Date Deposited: | 09 Jan 2025 13:08 |
| Last Modified: | 09 Jan 2025 13:08 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/25821 |
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