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

2024; American Association for the Advancement of Science; Volume: 10; Issue: 49 Linguagem: Inglês

10.1126/sciadv.adq1383

2375-2548

Paula Josefina Gómez, Anumeha Gupta, Laura Drought, Avnish Patel, John Okombo, Mariëtte van der Watt, Ryan Walker-Gray, Kyra A. Schindler, Anna Y. Burkhard, Tomas Yeo, Sunil Kumar Narwal, Talia S. Bloxham, Christian Flueck, Eloise M. Walker, Joshua A. Rey, Kate J. Fairhurst, Janette Reader, Heekuk Park, Harry Pollard, Lindsay B. Stewart, Luke Brandner-Garrod, Mojca Kristan, Geert-Jan Sterk, Youri M. van Nuland, Emilia Mańko, Donelly A. van Schalkwyk, Yang Zheng, Rob Leurs, Koen J. Dechering, Anna Caroline Campos Aguiar, Rafael V. C. Guido, Dhélio B. Pereira, Patrick K. Tumwebaze, Samuel L. Nosbya, Philip J. Rosenthal, Roland A. Cooper, Mark Palmer, Tanya Parkinson, Jeremy N. Burrows, Anne‐Catrin Uhlemann, Lyn‐Marié Birkholtz, Jennifer L. Small-Saunders, James Duffy, David A. Fidock, Alan Brown, Mark Gardner, David A. Baker,

Synthesis and Catalytic Reactions

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.