Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission

• Published in: Science advances 2024-12, Vol.10 (49), p.eadq1383
• Main Authors: 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 N, Uhlemann, Anne-Catrin, Birkholtz, Lyn-Marié, Small-Saunders, Jennifer L, Duffy, James, Fidock, David A, Brown, Alan, Gardner, Mark, Baker, David A
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - genetics; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Animals; Antimalarials - pharmacology; Culicidae - parasitology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Humans; Life Cycle Stages - drug effects; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Malaria, Falciparum - transmission; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - growth & development; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - genetics; Protozoan Proteins - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adq1383

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 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 PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline.