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Halofuginone (HF) has shown a significant anti\u2010<jats:italic>P.\u2005falciparum<\/jats:italic> effect, suggesting its potential as a therapeutic agent for malaria treatment. In this study, we synthesized a photoaffinity labeling probe of HF to identify its direct target in <jats:italic>P.\u2005falciparum<\/jats:italic>. Our results reveal that ubiquitin carboxyl\u2010terminal hydrolase 3 (PfUCHL3) acts as a crucial target protein of HF, which modulates parasite growth in the intraerythrocytic cycle. In particular, we discovered that HF potentially forms hydrogen bonds with the Leu10, Glu11, and Arg217 sites of PfUCHL3, thereby inducing an allosteric effect by promoting the embedding of the helix 6\u2019 region on the protein surface. Furthermore, HF disrupts the expression of multiple functional proteins mediated by PfUCHL3, specifically those that play crucial roles in amino acid biosynthesis and metabolism in <jats:italic>P.\u2005falciparum<\/jats:italic>. Taken together, this study highlights PfUCHL3 as a previously undisclosed druggable target of HF, which contributes to the development of novel anti\u2010malarial agents in the future.<\/jats:p>","DOI":"10.1002\/cbic.202400269","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T12:28:46Z","timestamp":1719232126000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemoproteomic Strategy Identifies PfUCHL3 as the Target of Halofuginone"],"prefix":"10.1002","volume":"25","author":[{"given":"Si\u2010Miao","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei\u2010Mei","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong\u2010Zhe","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u2010Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng\u2010Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Academy of Pharmaceutical Sciences Shandong Engineering Research Center of New Sustained and Controlled Release Formulations and Drug Targeted Delivery Systems  Jinan 250101 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng\u2010Fei","family":"Tu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College  5# Dong Dan San Tiao Beijing 100005 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun\u2010Yan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College  5# Dong Dan San Tiao Beijing 100005 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-6327","authenticated-orcid":false,"given":"Ke\u2010Wu","family":"Zeng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"e_1_2_9_1_1","first-page":"270","volume":"106","author":"Shahbodaghi S. \u20ac.","year":"2022","journal-title":"Am. 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