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

dc.contributor.authorGomez-Gonzalez, Paula-Josefina
dc.contributor.authorGupta, Antima
dc.contributor.authorDrought, Laura G.
dc.contributor.authorPatel, Avnish
dc.contributor.authorOkombo, John
dc.contributor.authorVan der Watt, Mariette Elizabeth
dc.contributor.authorWalker-Gray, Ryan
dc.contributor.authorSchindler, Kyra A.
dc.contributor.authorBurkhard, Anna Y.
dc.contributor.authorYeo, Tomas
dc.contributor.authorNarwal, Sunil K.
dc.contributor.authorBloxham, Talia S.
dc.contributor.authorFlueck, Christian
dc.contributor.authorWalker, Eloise M.
dc.contributor.authorRey, Joshua A.
dc.contributor.authorFairhurst, Kate J.
dc.contributor.authorReader, Janette
dc.contributor.authorPark, Heekuk
dc.contributor.authorPollard, Harry G.
dc.contributor.authorStewart, Lindsay B.
dc.contributor.authorBrandner-Garrod, Luke
dc.contributor.authorKristan, Mojca
dc.contributor.authorSterk, Geert-Jan
dc.contributor.authorVan Nuland, Youri M.
dc.contributor.authorManko, Emilia
dc.contributor.authorVan Schalkwyk, Donelly A.
dc.contributor.authorZheng, Yang
dc.contributor.authorLeurs, Rob
dc.contributor.authorDechering, Koen J.
dc.contributor.authorAguiar, Anna Caroline C.
dc.contributor.authorGuido, Rafael V.C.
dc.contributor.authorPereira, Dhelio B.
dc.contributor.authorTumwebaze, Patrick K.
dc.contributor.authorNosbya, Samuel L.
dc.contributor.authorRosenthal, Philip J.
dc.contributor.authorCooper, Roland A.
dc.contributor.authorPalmer, Mike
dc.contributor.authorParkinson, Tanya
dc.contributor.authorBurrows, Jeremy N.
dc.contributor.authorUhlemann, Anne-Catrin
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.authorSmall-Saunders, Jennifer L.
dc.contributor.authorDuffy, James
dc.contributor.authorFidock, David A.
dc.contributor.authorBrown, Alan
dc.contributor.authorGardner, Mark
dc.contributor.authorBaker, David A.
dc.date.accessioned2025-07-02T07:40:33Z
dc.date.available2025-07-02T07:40:33Z
dc.date.issued2024-10-06
dc.descriptionDATA 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.abstractCyclic 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.departmentBiochemistry, Genetics and Microbiology (BGM)
dc.description.departmentUP Centre for Sustainable Malaria Control (UP CSMC)
dc.description.librarianam2025
dc.description.sdgSDG-03: Good health and well-being
dc.description.sdgSDG-02: Zero Hunger
dc.description.sponsorshipThe 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.urihttps://www.science.org/journal/sciadv
dc.identifier.citationGomez-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.issn2375-2548
dc.identifier.other10.1126/sciadv.adq1383
dc.identifier.urihttp://hdl.handle.net/2263/103101
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.rights© 2024 The Authors. Distributed under a creative commons Attribution license 4.0 (cc BY).
dc.subjectInhibitors
dc.subjectMalaria
dc.subjectPhosphodiesterases (PDEs)
dc.subjectAntimalarial drug targets
dc.titleInhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission
dc.typeArticle

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