{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T16:49:54Z","timestamp":1793810994059,"version":"4.6.1"},"reference-count":67,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"49","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,12,6]]},"abstract":"<jats:p>\n            Cyclic nucleotide\u2013dependent 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\n            <jats:italic>Plasmodium falciparum<\/jats:italic>\n            PDE\u03b2 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 PDE\u03b2 but rather mutations in downstream effectors: either the catalytic or regulatory subunits of cyclic adenosine monophosphate\u2013dependent protein kinase (PKA) or in the 3-phosphoinositide-dependent protein kinase that is required for PKA activation. Several properties of these\n            <jats:italic>P. falciparum<\/jats:italic>\n            PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adq1383","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T18:58:44Z","timestamp":1733511524000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3670-8786","authenticated-orcid":true,"given":"Paula-Josefina","family":"Gomez-Gonzalez","sequence":"first","affiliation":[{"name":"Faculty of Infectious and Tropical Diseases, London School of Hygiene &amp; Tropical Medicine, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2145-4179","authenticated-orcid":true,"given":"Antima","family":"Gupta","sequence":"additional","affiliation":[{"name":"Faculty of Infectious and Tropical Diseases, London School of Hygiene &amp; 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