{"doi":"10.1126/sciadv.adq1383","title":"Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission","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.","journal":"Science Advances","year":2024,"id":466841,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1298958,"name":"Antima Gupta","orcid":"0009-0009-2145-4179","position":1,"is_corresponding":false},{"id":1298959,"name":"Laura Drought","orcid":"0000-0002-6290-5900","position":2,"is_corresponding":false},{"id":314780,"name":"Avnish Patel","orcid":"0000-0002-3608-3405","position":3,"is_corresponding":false},{"id":301617,"name":"John Okombo","orcid":"0000-0001-8680-2351","position":4,"is_corresponding":false},{"id":395744,"name":"Mariëtte van der Watt","orcid":"0000-0002-9933-8647","position":5,"is_corresponding":false},{"id":1299358,"name":"Ryan Walker-Gray","orcid":null,"position":6,"is_corresponding":false},{"id":679738,"name":"Kyra A. 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