{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:40:05Z","timestamp":1789666805699,"version":"4.0.1"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Thailand Science Research and Innovation Fundamental Fund","award":["TUFF13\/2564"],"award-info":[{"award-number":["TUFF13\/2564"]}]},{"DOI":"10.13039\/501100005790","name":"Thammasat University","doi-asserted-by":"publisher","award":["Thammasat University Research Unit in Antimicrobial Agents and Application"],"award-info":[{"award-number":["Thammasat University Research Unit in Antimicrobial Agents and Application"]}],"id":[{"id":"10.13039\/501100005790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005790","name":"Thammasat University","doi-asserted-by":"publisher","award":["Research Assistant Ph.D. grant"],"award-info":[{"award-number":["Research Assistant Ph.D. grant"]}],"id":[{"id":"10.13039\/501100005790","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Mitochondria are considered a novel drug target as they play a key role in energy production and programmed cell death of eukaryotic cells. The mitochondria of malaria parasites differ from those of their vertebrate hosts, contributing to the drug selectivity and the development of antimalarial drugs. (Fxr)3, a mitochondria-penetrating peptide or MPP, entered malaria-infected red cells without disrupting the membrane and subsequently killed the blood stage of P. falciparum parasites. The effects were more potent on the late stages than on the younger stages. Confocal microscopy showed that the (Fxr)3 intensely localized at the parasite mitochondria. (Fxr)3 highly affected both the lab-strain, chloroquine-resistant K1, and freshly isolated malaria parasites. (Fxr)3 (1 ng\/mL to 10 \u03bcg\/mL) was rarely toxic towards various mammalian cells, i.e., mouse fibroblasts (L929), human leukocytes and erythrocytes. At a thousand times higher concentration (100 \u03bcg\/mL) than that of the antimalarial activity, cytotoxicity and hemolytic activity of (Fxr)3 were observed. Compared with the known antimalarial drug, atovaquone, (Fxr)3 exhibited more rapid killing activity. This is the first report on antimalarial activity of (Fxr)3, showing localization at parasites\u2019 mitochondria.<\/jats:p>","DOI":"10.3390\/antibiotics10121560","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"1560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Mitochondria-Penetrating Peptide Exerts Potent Anti-Plasmodium Activity and Localizes at Parasites\u2019 Mitochondria"],"prefix":"10.3390","volume":"10","author":[{"given":"Sangdao","family":"Somsri","sequence":"first","affiliation":[{"name":"Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathirut","family":"Mungthin","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Phramongkutklao College of Medicine, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natthaporn","family":"Klubthawee","sequence":"additional","affiliation":[{"name":"Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poom","family":"Adisakwattana","sequence":"additional","affiliation":[{"name":"Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-8218","authenticated-orcid":false,"given":"Warunee","family":"Hanpithakpong","sequence":"additional","affiliation":[{"name":"Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratchaneewan","family":"Aunpad","sequence":"additional","affiliation":[{"name":"Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani 12120, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021, October 10). The \u201cWorld Malaria Report 2019\u201d at a Glance. Available online: https:\/\/www.who.int\/news-room\/feature-stories\/detail\/world-malaria-report-2019."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2012026","DOI":"10.4084\/mjhid.2012.026","article-title":"Clinical aspects of uncomplicated and severe malaria","volume":"4","author":"Bartoloni","year":"2012","journal-title":"Medit. J. Hematol. Inf. Dis."},{"key":"ref_3","unstructured":"World Health Organization (2013). Emergency Response to Artemisinin Resistance in the Greater Mekong Subregion: Regional Framework for Action 2013\u20132015, WHO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.parint.2011.02.001","article-title":"Highly conserved gene arrangement of the mitochondrial genomes of 23 Plasmodium species","volume":"60","author":"Hikosaka","year":"2011","journal-title":"Parasitol. Inter."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1074\/jbc.272.7.3961","article-title":"Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite","volume":"272","author":"Srivastava","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1093\/jac\/dkm337","article-title":"A systematic review and meta-analysis of the effectiveness and safety of atovaquone proguanil (Malarone) for chemoprophylaxis against malaria","volume":"60","author":"Nakato","year":"2007","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-015-0974-y","article-title":"New linear antiplasmodial peptides related to angiotensin II","volume":"14","author":"Silva","year":"2015","journal-title":"Malar. J."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Maciel, C., Junior, V.X.D., F\u00e1zio, M.A., Nacif-Pimenta, R., Miranda, A., Pimenta, P.F.P., and Capurro, M.L. (2008). Anti-plasmodium activity of angiotensin II and related synthetic peptides. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003296"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/j.chembiol.2012.09.020","article-title":"The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains","volume":"19","author":"Stolze","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.2174\/138945012802002393","article-title":"Antimicrobial peptide action on parasites","volume":"13","author":"Torrent","year":"2012","journal-title":"Curr. Drug Targets"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3389\/fphar.2014.00275","article-title":"Antimicrobial peptides: A new class of antimalarial drugs?","volume":"5","author":"Vale","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1128\/AAC.44.9.2442-2451.2000","article-title":"Antimalarial activities of dermaseptin S4 derivatives","volume":"44","author":"Krugliak","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ijpara.2005.11.003","article-title":"Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action","volume":"36","author":"Bell","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.chembiol.2008.03.015","article-title":"Mitochondria-penetrating peptides","volume":"15","author":"Horton","year":"2008","journal-title":"Chem. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.bbamem.2013.03.027","article-title":"Observing the translocation of a mitochondria-penetrating peptide with solid-state NMR","volume":"1828","author":"Marbella","year":"2013","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0304-4157(94)90004-3","article-title":"Permeation of hydrophilic solutes through mitochondrial outer membranes: Review on mitochondrial porins","volume":"1197","author":"Benz","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-021-23919-x","article-title":"Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum","volume":"12","author":"Evers","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/9486905","article-title":"Antimalarial Activity of Piperine","volume":"2018","author":"Thiengsusuk","year":"2018","journal-title":"J. Trop. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7360","DOI":"10.1021\/acs.jmedchem.5b01380","article-title":"Artemisinin-derived dimers: Potent antimalarial and anticancer agents","volume":"59","author":"Reiter","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1046\/j.1365-2958.1999.01515.x","article-title":"Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites","volume":"33","author":"Srivastava","year":"1999","journal-title":"Mol. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm.4381","article-title":"Antimalarial drug resistance: Linking Plasmodium falciparum parasite biology to the clinic","volume":"23","author":"Blasco","year":"2017","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.chembiol.2013.08.010","article-title":"Targeting mitochondrial DNA with a platinum-based anticancer agent","volume":"20","author":"Wisnovsky","year":"2013","journal-title":"Chem. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1006\/expr.1995.1049","article-title":"Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro","volume":"80","author":"Canfield","year":"1995","journal-title":"Exp. Parasitol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1093\/molbev\/mst104","article-title":"The Evolutionary History of Plasmodium vivax as Inferred from Mitochondrial Genomes: Parasite Genetic Diversity in the Americas","volume":"30","author":"Taylor","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s00508-011-0044-6","article-title":"Sensitivity of Plasmodium vivax to chloroquine, mefloquine, artemisinin and atovaquone in north-western Thailand","volume":"1","author":"Treiber","year":"2011","journal-title":"Wien Klin. Wochenschr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.chembiol.2011.02.010","article-title":"Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells","volume":"18","author":"Fonseca","year":"2011","journal-title":"Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1158\/1535-7163.MCT-16-0048","article-title":"Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma","volume":"15","author":"Buondonno","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kalafatovic, D., and Giralt, E. (2017). Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity. Molecules, 22.","DOI":"10.3390\/molecules22111929"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"883","DOI":"10.2307\/3279900","article-title":"Plasmodium falciparum in culture: Uuse of outdated erythrocytes and description of the candle jar method","volume":"63","author":"Jensen","year":"1977","journal-title":"J. Parasitol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1128\/AAC.16.6.710","article-title":"Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique","volume":"16","author":"Desjardins","year":"1979","journal-title":"Antimicrob. 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