{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:30:19Z","timestamp":1787567419366,"version":"build-2736575974"},"reference-count":125,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["F32 AI188627"],"award-info":[{"award-number":["F32 AI188627"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"award":["F32 AI188627"],"award-info":[{"award-number":["F32 AI188627"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["T32AI007172"],"award-info":[{"award-number":["T32AI007172"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"award":["T32AI007172"],"award-info":[{"award-number":["T32AI007172"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Artemisinin-based combination therapies (ACTs) remain the mainstay of treatment for\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    malaria, despite reports of ACT treatment failure. ACTs consist of an artemisinin and a longer-lived partner drug, which is often a quinoline. Given that heme is central to the mechanism of action of artemisinins and some quinolines, we hypothesized that these antimalarials would exhibit strong drug-drug interactions. Previous studies using standard 48 hr or 72 hr assays identified additive to mildly antagonistic interactions between artemisinins and quinolines. Here, we sought to re-evaluate these interactions using a pulsing assay that better mimics the short in vivo half-life of artemisinins. We found that chloroquine (CQ), piperaquine (PPQ), and amodiaquine substantially antagonize dihydroartemisinin (DHA), the active metabolite of artemisinins. CQ-DHA antagonism was notably exacerbated in CQ-resistant parasites, resulting in a superantagonistic phenotype in isobolograms. Further, we found that CQ co-treatment conferred artemisinin resistance to Kelch 13 wild-type parasites in the ring-stage survival assay. Using a small molecule probe (Ac-H-FluNox) to measure chemically reactive heme in live parasites, we determined that quinolines block artemisinin activation by rendering cytosolic heme inert. Finally, we probed beyond traditional ACTs, evaluating interactions of the proposed triple ACT, DHA-PPQ-mefloquine, as well as OZ439-quinoline combinations, which were all found to be antagonistic. Collectively, these in vitro data suggest that peroxide-quinolines may have liabilities as combination therapies.\n                  <\/jats:p>","DOI":"10.7554\/elife.108976","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T11:30:43Z","timestamp":1762255843000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108976","source":"Crossref","is-referenced-by-count":1,"title":["4-Aminoquinolines block heme iron reactivity and interfere with artemisinin action"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4490-6010","authenticated-orcid":true,"given":"Melissa","family":"Rosenthal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, Washington University School of Medicine","place":["Saint Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3529-8399","authenticated-orcid":true,"given":"Daniel E","family":"Goldberg","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, Washington University School of Medicine","place":["Saint Louis, United States"]},{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["Saint Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"E2068","DOI":"10.1073\/pnas.1615195114","type":"journal-article","article-title":"Quantification of labile heme in live malaria parasites using a genetically encoded biosensor","volume":"114","author":"Abshire","year":"2017","journal-title":"PNAS"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/0162-0134(95)00212-x","type":"journal-article","article-title":"The iron environment in heme and heme-antimalarial complexes of pharmacological interest","volume":"63","author":"Adams","year":"1996","journal-title":"Journal of Inorganic Biochemistry"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-021-03749-4","type":"journal-article","article-title":"A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria","volume":"20","author":"Adoke","year":"2021","journal-title":"Malaria Journal"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S1473-3099(15)00487-9","type":"journal-article","article-title":"Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study","volume":"16","author":"Amaratunga","year":"2016","journal-title":"The Lancet. 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