{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:21:54Z","timestamp":1781108514527,"version":"3.54.1"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:00:00Z","timestamp":1739836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["R01 AI154777"],"award-info":[{"award-number":["R01 AI154777"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-039628"],"award-info":[{"award-number":["INV-039628"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,25]]},"abstract":"<jats:p>\n                    Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus\n                    <jats:italic>Trichocladium asperum<\/jats:italic>\n                    that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    with the most potent member, NPDG-F (EC\n                    <jats:sub>50<\/jats:sub>\n                    of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure\u2013activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2418871122","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T11:40:41Z","timestamp":1739878841000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Fungal-derived methyldeoxaphomins target\n                    <i>Plasmodium falciparum<\/i>\n                    segregation through the inhibition of PfActin1"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4875-3613","authenticated-orcid":false,"given":"Tiantian","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-0884","authenticated-orcid":false,"given":"Jin Woo","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Duksung Women\u2019s University","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Collins","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida","place":["Orlando"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flore","family":"Nardella","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida","place":["Orlando"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Wendt","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Michigan","place":["Ann Arbor"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilini G.","family":"Peramuna","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Michigan","place":["Ann Arbor"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6146-5309","authenticated-orcid":false,"given":"Raphaella","family":"Paes","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida","place":["Orlando"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"McLellan","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3503-3326","authenticated-orcid":false,"given":"Jasveen","family":"Bhasin","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida","place":["Orlando"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7188-1347","authenticated-orcid":false,"given":"Gregory L.","family":"Durst","sequence":"additional","affiliation":[{"name":"Lgenia Inc.","place":["Fortville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0154-0979","authenticated-orcid":false,"given":"Kirsten K.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-3119","authenticated-orcid":false,"given":"Debopam","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida","place":["Orlando"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Cichewicz","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Michigan","place":["Ann Arbor"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Winzeler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California","place":["San Diego"]},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00283"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0269391"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00772-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2021.107866"},{"key":"e_1_3_4_5_2","volume-title":"Discovery of Aantiplasmodial Compounds from Fungi","author":"Collins J.","year":"2022","unstructured":"J. Collins, Discovery of Aantiplasmodial Compounds from Fungi (University of Central Florida, Orlando, FL, 2022)."},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.4c00232"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.3c00283"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","DOI":"10.1128\/spectrum.04142-23","article-title":"Identification of fungal natural products with potent inhibition in Toxoplasma gondii","volume":"10","author":"Jiang T.","year":"2024","unstructured":"T. Jiang , Identification of fungal natural products with potent inhibition in Toxoplasma gondii. Microbiol. Spectr. 10, e0414223 (2024).","journal-title":"Microbiol. Spectr."},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.1c00341"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.0c01370"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.104317"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030949"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38774-1"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010408"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.09.082"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81071-5"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-017-0406-2"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004091"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3285"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1906600116"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11330-w"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002066"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011157"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915987117"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.06.063"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2004.09.004"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-042910-155359"},{"key":"e_1_3_4_28_2","unstructured":"T. Jiang Whole genome sequencing of Trichocladium asperum gDNA; WGS of Plasmodium falciparum: Methyldeoxaphomin NPDG F-resistant clones and Dd2-Pol-delta. Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/sra\/?term=PRJNA1112907. Deposited 17 August 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2418871122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T11:41:39Z","timestamp":1739878899000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2418871122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,18]]},"references-count":28,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,2,25]]}},"alternative-id":["10.1073\/pnas.2418871122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2418871122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,18]]},"assertion":[{"value":"2024-09-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2418871122"}}