{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:54:20Z","timestamp":1791302060777,"version":"4.1.0"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"39","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFE0116600"],"award-info":[{"award-number":["2024YFE0116600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-KJ-017"],"award-info":[{"award-number":["2025-I2M-KJ-017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Artemisinin and Yingzhaosu A (YZSA), two endoperoxide-containing natural products with antimalarial activity discovered through China\u2019s historic 523 Project, have long been the focus of global antimalarial research. Many scientific studies have proposed that their endoperoxide bridges are activated by heme (not hemoglobin) to generate active carbon radicals, which subsequently eliminate the parasite. However, we discovered that X-2b, a YZSA-structured turn-on fluorescent probe previously reported by our group, exhibited stronger reactivity toward hemoglobin than toward heme, a finding that prompted us to revisit and refine our previously reported conclusions. Herein, we present a systematic investigation into the reactivity of several representative endoperoxide-containing compounds toward heme and hemoglobin. The investigated endoperoxides show distinct reactivity toward heme versus hemoglobin. Notably, compounds showing high reactivity toward hemoglobin display diminished antimalarial activity. This study challenges the prevailing mechanistic paradigm and sheds new light on the mode of action of endoperoxide-containing antimalarials.<\/jats:p>","DOI":"10.1021\/acsomega.6c05579","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:01:51Z","timestamp":1790128911000},"page":"59454-59462","source":"Crossref","is-referenced-by-count":0,"title":["Endoperoxides Show\nDistinct Reactivity toward Heme\nand Hemoglobin"],"prefix":"10.1021","volume":"11","author":[{"given":"Shuang","family":"Wang","sequence":"first","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College , , ,","place":["Beijing, China, 100050"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiubo","family":"Sun","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College , , ,","place":["Beijing, China, 100050"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Wei","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , 5# Dong Dan San Tiao , ,","place":["Beijing, China, 100005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3396-9999","authenticated-orcid":true,"given":"Chong-Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College , , ,","place":["Beijing, China, 100050"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"2026100610474902300_cit1","volume-title":"Licence: cC BY-NC-SA\n3.0 World Health Or ganization","author":"World malaria report 2025: addressing the threat of antimalarial drug resistance.","year":"2025"},{"key":"2026100610474902300_cit2","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1039\/C5NP00133A","article-title":"Artemisinin, a miracle\nof traditional Chinese medicine","volume":"32","author":"Kong","year":"2015","journal-title":"Nat. Prod.\nRep."},{"key":"2026100610474902300_cit3","doi-asserted-by":"publisher","first-page":"10210","DOI":"10.1002\/anie.201601967","article-title":"Artemisinin-A\nGift from Traditional Chinese Medicine to the World (Nobel Lecture)","volume":"55","author":"Tu","year":"2016","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026100610474902300_cit4","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2026100610474902300_cit5","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1016\/S0140-6736(23)01249-7","article-title":"Malaria","volume":"402","author":"Poespoprodjo","year":"2023","journal-title":"The Lancet"},{"key":"2026100610474902300_cit6","article-title":"Risk of selection\nand timelines for the continued spread of artemisinin and partner\ndrug resistance in Africa","author":"Watson","year":"2024","journal-title":"medRxiv"},{"key":"2026100610474902300_cit7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1093\/femsre\/fuw037","article-title":"The clinical impact\nof artemisinin resistance in Southeast\nAsia and the potential for future spread","volume":"41","author":"Woodrow","year":"2017","journal-title":"FEMS\nMicrobiol. Re.v"},{"key":"2026100610474902300_cit8","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1001\/jama.2024.23100","article-title":"Artemisinin\nPartial Resistance and the Treatment of Severe Malaria","volume":"333","author":"Rosenthal","year":"2025","journal-title":"JAMA"},{"key":"2026100610474902300_cit9","doi-asserted-by":"publisher","first-page":"86","DOI":"10.4103\/tp.TP_12_19","article-title":"A study on multi-organ dysfunction\nsyndrome in malaria using sequential organ failure assessment score","volume":"10","author":"Bhutani","year":"2020","journal-title":"Trop. Parasitol"},{"key":"2026100610474902300_cit10","doi-asserted-by":"publisher","DOI":"10.5694\/mja2.70136","article-title":"Treatment Failure and Post-Artesunate\nDelayed Haemolysis in a Returned Traveller From Uganda With Partially\nDrug-Resistant Severe Plasmodium falciparum Malaria","volume":"224","author":"Travis","year":"2026","journal-title":"Med. J. Aust."},{"key":"2026100610474902300_cit11","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1001\/jama.2024.22343","article-title":"Artemisinin Partial Resistance in Ugandan Children\nWith Complicated Malaria","volume":"333","author":"Henrici","year":"2025","journal-title":"JAMA"},{"issue":"2","key":"2026100610474902300_cit12","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00104-19","article-title":"Imported Malaria\nin Countries where Malaria Is Not\nEndemic: a Comparison of Semi-immune and Nonimmune Travelers","volume":"33","author":"JohannesMischlinger","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"2026100610474902300_cit13","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of artemisinin resistance in Plasmodium falciparum\nmalaria","volume":"371","author":"Ashley","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"2026100610474902300_cit14","doi-asserted-by":"publisher","first-page":"102193","DOI":"10.1016\/j.mib.2022.102193","article-title":"Plasmodium\nfalciparum resistance\nto artemisinin-based combination therapies","volume":"69","author":"Ward","year":"2022","journal-title":"Curr. Opin. Microbiol"},{"key":"2026100610474902300_cit15","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1093\/cid\/ciw388","article-title":"Declining Efficacy of Artemisinin Combination Therapy\nAgainst P. Falciparum Malaria on the Thai-Myanmar Border (2003\u20132013):\nThe Role of Parasite Genetic Factors","volume":"63","author":"Phyo","year":"2016","journal-title":"Clin.\nInfect. Dis."},{"key":"2026100610474902300_cit16","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2147\/IDR.S7454","article-title":"Acquired\nresistance of malarial parasites against artemisinin-based\ndrugs: social and economic impacts","volume":"3","author":"Porter-Kelley","year":"2010","journal-title":"Infect.\nDrug. Resist"},{"key":"2026100610474902300_cit17","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1186\/1475-2875-13-452","article-title":"Artemisinin\nresistance \u2013 modelling the potential human and economic costs","volume":"13","author":"Lubell","year":"2014","journal-title":"Malar. J"},{"key":"2026100610474902300_cit18","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03169-23","article-title":"Oxidative stress\nchanges the effectiveness of artemisinin\nin Plasmodium falciparum","volume":"15","author":"Pires","year":"2024","journal-title":"mBio"},{"key":"2026100610474902300_cit19","doi-asserted-by":"publisher","first-page":"5968","DOI":"10.1021\/ja970412g","article-title":"Characterization of the First Covalent\nAdduct between\nArtemisinin and a Heme Model","volume":"119","author":"Robert","year":"1997","journal-title":"J. Am. Chem. Soc"},{"key":"2026100610474902300_cit20","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0014-5793(03)01448-0","article-title":"Alkylation of human\nhemoglobin A0 by the antimalarial drug artemisinin","volume":"556","author":"Selmeczi","year":"2004","journal-title":"FEBS Lett"},{"key":"2026100610474902300_cit21","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1002\/1439-7633(20021104)3:11&lt;1147::AID-CBIC1147&gt;3.0.CO;2-8","article-title":"Alkylation\nof Microperoxidase-11\nby the Antimalarial Drug Artemisinin","volume":"3","author":"Rodriguez","year":"2002","journal-title":"ChemBiochem"},{"key":"2026100610474902300_cit22","doi-asserted-by":"publisher","first-page":"10111","DOI":"10.1038\/ncomms10111","article-title":"Haem-activated promiscuous targeting\nof artemisinin in Plasmodium falciparum","volume":"6","author":"Wang","year":"2015","journal-title":"Nat.\nCommun."},{"key":"2026100610474902300_cit23","doi-asserted-by":"publisher","first-page":"9535","DOI":"10.1039\/C9CC03719E","article-title":"Activity-based protein\nprofiling reveals that secondary-carbon-centered radicals of synthetic\n1,2,4-trioxolanes are predominately responsible for modification of\nprotein targets in malaria parasites","volume":"55","author":"Wei","year":"2019","journal-title":"Chem.\nCommun."},{"key":"2026100610474902300_cit24","doi-asserted-by":"publisher","first-page":"6401","DOI":"10.1002\/anie.201512062","article-title":"A Click\nChemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and\nArtemisinin Antimalarials Share a Common Protein Alkylation Profile","volume":"55","author":"Ismail","year":"2016","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026100610474902300_cit25","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1073\/pnas.1600459113","article-title":"Artemisinin activity-based probes identify multiple\nmolecular targets within the asexual stage of the malaria parasites\nPlasmodium falciparum 3D7","volume":"113","author":"Ismail","year":"2016","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"key":"2026100610474902300_cit26","doi-asserted-by":"publisher","first-page":"4046","DOI":"10.1128\/AAC.00183-15","article-title":"Stability of the antimalarial drug dihydroartemisinin\nunder physiologically relevant conditions: implications for clinical\ntreatment and pharmacokinetic and in vitro assays","volume":"59","author":"Parapini","year":"2015","journal-title":"Antimicrob. Agents Chemother"},{"key":"2026100610474902300_cit27","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1021\/acsinfecdis.9b00430","article-title":"A Chemically Stable Fluorescent Mimic\nof Dihydroartemisinin, Artemether, and Arteether with Conserved Bioactivity\nand Specificity Shows High Pharmacological Relevance to the Antimalarial\nDrugs","volume":"6","author":"Sissoko","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"2026100610474902300_cit28","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01566-17","article-title":"Parasite-Mediated\nDegradation of Synthetic Ozonide\nAntimalarials Impacts In Vitro Antimalarial Activity","volume":"62","author":"Giannangelo","year":"2018","journal-title":"Antimicrob. Agents Chemother"},{"key":"2026100610474902300_cit29","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00143-24","article-title":"Characterization\nof antimalarial activity of artemisinin-based hybrid drugs","volume":"68","author":"Quadros","year":"2024","journal-title":"Antimicrob. Agents Chemother"},{"key":"2026100610474902300_cit30","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/s41392-022-00961-9","article-title":"A heme-activatable\nprobe and its application in the high-throughput screening of Plasmodium\nfalciparum ring-stage inhibitors","volume":"7","author":"Liu","year":"2022","journal-title":"Signal Transduction\nTargeted Ther."},{"key":"2026100610474902300_cit31","first-page":"215","article-title":"The structure of\nyingzhaosu A","volume":"37","author":"Liang","year":"1979","journal-title":"Acta Chim. Sin"},{"key":"2026100610474902300_cit32","doi-asserted-by":"publisher","first-page":"3793","DOI":"10.1021\/jacs.1c08485","article-title":"Molecular Imaging of\nLabile Heme\nin Living Cells Using a Small Molecule Fluorescent Probe","volume":"144","author":"Kawai","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"2026100610474902300_cit33","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1021\/acssensors.4c00010","article-title":"A Radical-Generating Probe to Release\nFree Fluorophores and Identify Artemisinin-Sensitive Cancer Cells","volume":"9","author":"Chen","year":"2024","journal-title":"ACS Sens"},{"key":"2026100610474902300_cit34","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.pt.2019.05.002","article-title":"Ozonide\nAntimalarial Activity in the Context of Artemisinin-Resistant Malaria","volume":"35","author":"Giannangelo","year":"2019","journal-title":"Trends Parasitol"},{"key":"2026100610474902300_cit35","doi-asserted-by":"publisher","first-page":"831","DOI":"10.2174\/1568026619666190412104042","article-title":"Recent Developments\nin Natural Product\nInspired Synthetic 1,2,4- Trioxolanes (Ozonides): An Unusual Entry\ninto Antimalarial Chemotherapy","volume":"19","author":"Tiwari","year":"2019","journal-title":"Curr. Top. Med.\nChem."},{"key":"2026100610474902300_cit36","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S1473-3099(15)00320-5","article-title":"Antimalarial activity of artefenomel\n(OZ439), a novel synthetic antimalarial endoperoxide, in patients\nwith Plasmodium falciparum and Plasmodium vivax malaria: an open-label\nphase 2 trial","volume":"16","author":"Phyo","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"2026100610474902300_cit37","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1093\/jac\/dkw174","article-title":"Efficacy of OZ439\n(artefenomel) against early Plasmodium falciparum blood-stage malaria\ninfection in healthy volunteers","volume":"71","author":"McCarthy","year":"2016","journal-title":"J. Antimicrob.\nChemother"},{"key":"2026100610474902300_cit38","doi-asserted-by":"publisher","first-page":"119","DOI":"10.4269\/ajtmh.2004.70.119","article-title":"A novel DNA-based\nmicrofluorimetric method to evaluate antimalarial drug activity","volume":"70","author":"Corbett","year":"2004","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2026100610474902300_cit39","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1128\/AAC.00527-15","article-title":"Assessment of the Worldwide Antimalarial Resistance\nNetwork Standardized Procedure for In Vitro Malaria Drug Sensitivity\nTesting Using SYBR Green Assay for Field Samples with Various Initial\nParasitemia Levels","volume":"60","author":"Cheruiyot","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026100610474902300_cit40","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1186\/s12936-022-04301-8","article-title":"Severe\nmalaria","volume":"21","author":"White","year":"2022","journal-title":"Malar. J."},{"key":"2026100610474902300_cit41","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1056\/NEJMra2405313","article-title":"Malaria","volume":"392","author":"Daily","year":"2025","journal-title":"N. Engl. J. Med."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c05579","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/39\/59454\/68611191\/acsomega.6c05579.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/39\/59454\/68611191\/acsomega.6c05579.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:10:25Z","timestamp":1791299425000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/39\/59454\/5436015\/Endoperoxides-Show-Distinct-Reactivity-toward-Heme"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":41,"journal-issue":{"issue":"39","published-online":{"date-parts":[[2026,9,22]]},"published-print":{"date-parts":[[2026,10,6]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c05579","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]}}}