{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:55:53Z","timestamp":1772117753859,"version":"3.50.1"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2017\/224521"],"award-info":[{"award-number":["2017\/224521"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2022\/095264"],"award-info":[{"award-number":["2022\/095264"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2023\/123431"],"award-info":[{"award-number":["2023\/123431"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2024\/099972"],"award-info":[{"award-number":["2024\/099972"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Letters"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Ubiquinone (UQ) is essential for the electron transport chain in\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    , the causative agent of severe malaria. Its biosynthesis begins with the condensation of 4\u2010hydroxybenzoate (4\u2010HB) and an isoprenoid chain, catalyzed by 4\u2010HB polyprenyltransferase (4\u2010HPT;\n                    <jats:italic>COQ2<\/jats:italic>\n                    gene). Atovaquone (AV) inhibits the mitochondrial bc1 complex by competing with ubiquinol (UQH\n                    <jats:sub>2<\/jats:sub>\n                    ), but resistance to the synergic combination AV\/proguanil therapy has emerged. Here, we show that 4\u2010nitrobenzoate (4\u2010NB) inhibits\n                    <jats:italic>Pf<\/jats:italic>\n                    4\u2010HPT, enhances AV efficacy and selectivity, while preserving proguanil synergy. In\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    expressing\n                    <jats:italic>PfCOQ2<\/jats:italic>\n                    , 4\u2010NB inhibited UQ biosynthesis.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , 4\u2010NB improved AV efficacy in\n                    <jats:italic>Plasmodium berghei<\/jats:italic>\n                    \u2010infected mice. Structure\u2013activity studies with 4\u2010HB analogs further defined chemical features for potentiation. These findings support\n                    <jats:italic>PfCOQ2<\/jats:italic>\n                    as a target to boost AV\u2010based antimalarial therapy.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                      <jats:caption>\n                        <jats:title>Impact statement<\/jats:title>\n                      <\/jats:caption>\n                      <jats:p>\n                        This study identifies a molecular rationale for enhancing atovaquone efficacy through targeted inhibition of ubiquinone biosynthesis. By validating\n                        <jats:italic>PfCOQ2<\/jats:italic>\n                        as a druggable target and demonstrating\n                        <jats:italic>in vivo<\/jats:italic>\n                        potentiation, our findings offer strategic advance toward rational antimalarial combination therapies, moving beyond empirical approaches and addressing current resistance.\n                      <\/jats:p>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1002\/1873-3468.70186","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T06:40:44Z","timestamp":1760510444000},"page":"251-266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["4\u2010nitrobenzoate inhibits 4\u2010hydroxybenzoate polyprenyltransferase in malaria parasites and enhances atovaquone efficacy"],"prefix":"10.1002","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5625-5454","authenticated-orcid":false,"given":"Ignasi Bofill","family":"Verdaguer","sequence":"first","affiliation":[{"name":"Department of Parasitology, Institute of Biomedical Sciences University of S\u00e3o Paulo  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matheus Felipe","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Institute of Biomedical Sciences University of S\u00e3o Paulo  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maur\u00edcio Mazzine","family":"Filho","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Institute of Biomedical Sciences University of S\u00e3o Paulo  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela Oliveira","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Institute of Biomedical Sciences University of S\u00e3o Paulo  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agust\u00edn","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Betternostics S.L.  Noain Navarre Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoel Aparecido","family":"Peres","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Institute of Biomedical Sciences University of S\u00e3o Paulo  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-2162","authenticated-orcid":false,"given":"Alejandro Miguel","family":"Katzin","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Institute of Biomedical Sciences University of S\u00e3o Paulo  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-5471","authenticated-orcid":false,"given":"Marcell","family":"Crispim","sequence":"additional","affiliation":[{"name":"Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences Federal University of Alfenas  Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"World Malaria Report 2023","author":"World Health Organization","year":"2023"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.326.7390.628"},{"key":"e_1_2_11_4_1","first-page":"45","article-title":"Drug resistance in malaria","volume":"41","author":"Farooq U","year":"2004","journal-title":"J Vector Borne Dis"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)90671-6"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200363060-00006"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01516-20"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05572"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.6.1334"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1086\/375073"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1054\/drup.2000.0157"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0169-4758(94)90079-5"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2002.tb11021.x"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24203721"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-50319-5"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/femsle\/fnad050"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2006.00027.x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.781840"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1590\/0074-02760210331"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.2307\/3280287"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(97)00237-5"},{"key":"e_1_2_11_22_1","first-page":"87","volume-title":"Methods in Enzymology","author":"Gietz RD","year":"2002"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb1313s23"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(94)90193-7"},{"key":"e_1_2_11_25_1","volume-title":"Quinones and Quinone Enzymes, Part B","author":"Sies H","year":"2004"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.511709"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.16.6.710"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.5.1803-1806.2004"},{"key":"e_1_2_11_29_1","first-page":"1097","article-title":"Toxicit\u00e9s compar\u00e9es des acides nitrobenzo\u00efques pour la souris et le rat [Comparative toxicity of nitrobenzoic acids for mice and rats]","volume":"160","author":"Caujolle F","year":"1966","journal-title":"C R Seances Soc Biol Fil"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01867-16"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(83)90303-4"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8050130"},{"key":"e_1_2_11_33_1","first-page":"203","article-title":"Prevention and detection of mycoplasma contamination in cell culture","volume":"13","author":"Nikfarjam L","year":"2012","journal-title":"Cell J"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S37324"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00436"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(92)90051-K"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1938.s1-18.715"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9122"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.372"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030606"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11738-015-2043-0"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9452(00)00200-4"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(92)81425-L"},{"key":"e_1_2_11_44_1","first-page":"1","article-title":"Toxicology and carcinogenesis studies of p\u2010nitrobenzoic acid (CAS No. 62\u201023\u20107) in F344\/N rats and B6C3F1 mice","volume":"442","author":"National Toxicology Program (NTP)","year":"1994","journal-title":"NTP Tech Rep"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498258109049087"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(25)14691-9"},{"key":"e_1_2_11_47_1","article-title":"4\u2010nitrobenzoic acid. MAK collect","volume":"7","author":"Hartwig A","year":"2022","journal-title":"Occup Health Saf"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(75)90022-3"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.151894"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.93.2407.164"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(57)90023-8"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.2307\/3284461"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-018-6027-z"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/30.6.827"}],"container-title":["FEBS Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1873-3468.70186","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1873-3468.70186","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1873-3468.70186","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T12:47:28Z","timestamp":1769431648000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1873-3468.70186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":53,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/1873-3468.70186"],"URL":"https:\/\/doi.org\/10.1002\/1873-3468.70186","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v3\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1873-3468.70186\/v3\/decision1","asserted-by":"object"}]},"ISSN":["0014-5793","1873-3468"],"issn-type":[{"value":"0014-5793","type":"print"},{"value":"1873-3468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]},"assertion":[{"value":"2025-06-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}