{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T07:09:20Z","timestamp":1785395360433,"version":"3.55.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1F31HL154510, 5R21AI166478"],"award-info":[{"award-number":["1F31HL154510, 5R21AI166478"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chemotherapies for malaria and babesiosis frequently succumb to the emergence of pathogen-related drug-resistance. Host-targeted therapies are thought to be less susceptible to resistance but are seldom considered for treatment of these diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Our overall objective was to systematically assess small molecules for host cell-targeting activity to restrict proliferation of intracellular parasites. We carried out a literature survey to identify small molecules annotated for host factors implicated in <jats:italic>Plasmodium falciparum<\/jats:italic> infection. Alongside <jats:italic>P. falciparum<\/jats:italic>, we implemented <jats:italic>in vitro<\/jats:italic> parasite susceptibility assays also in the zoonotic parasite <jats:italic>Plasmodium knowlesi<\/jats:italic> and the veterinary parasite <jats:italic>Babesia divergens<\/jats:italic>. We additionally carried out assays to test directly for action on RBCs apart from the parasites. To distinguish specific host-targeting antiparasitic activity from erythrotoxicity, we measured phosphatidylserine exposure and hemolysis stimulated by small molecules in uninfected RBCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified diverse RBC target-annotated inhibitors with <jats:italic>Plasmodium<\/jats:italic>-specific, <jats:italic>Babesia-<\/jats:italic>specific, and broad-spectrum antiparasitic activity. The anticancer MEK-targeting drug trametinib is shown here to act with submicromolar activity to block proliferation of <jats:italic>Plasmodium<\/jats:italic> spp. in RBCs. Some inhibitors exhibit antimalarial activity with transient exposure to RBCs prior to infection with parasites, providing evidence for host-targeting activity distinct from direct inhibition of the parasite.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We report here characterization of small molecules for antiproliferative and host cell-targeting activity for malaria and babesiosis parasites. This resource is relevant for assessment of physiological RBC-parasite interactions and may inform drug development and repurposing efforts.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2024.1304839","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T10:56:29Z","timestamp":1710932189000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules"],"prefix":"10.3389","volume":"14","author":[{"given":"Patrice V.","family":"Groomes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya S.","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj T.","family":"Duraisingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4015","DOI":"10.1038\/s41467-020-17829-7","article-title":"Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention","volume":"11","author":"Adderley","year":"2020","journal-title":"Nat. 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