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We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3\u2013LC3 interaction, thus inhibiting the parasite\u2019s ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host\u2013parasite interaction without affecting the host\u2019s normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.<\/jats:p>","DOI":"10.1038\/s42003-020-01422-1","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T11:03:51Z","timestamp":1605783831000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Disrupting Plasmodium UIS3\u2013host LC3 interaction with a small molecule causes parasite elimination from host cells"],"prefix":"10.1038","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6673-5240","authenticated-orcid":false,"given":"Sonali","family":"Setua","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8072-8557","authenticated-orcid":false,"given":"Francisco J.","family":"Enguita","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7941-7196","authenticated-orcid":false,"given":"\u00c2ngelo Ferreira","family":"Chora","sequence":"additional","affiliation":[]},{"given":"Harish","family":"Ranga-prasad","sequence":"additional","affiliation":[]},{"given":"Aparajita","family":"Lahree","sequence":"additional","affiliation":[]},{"given":"Sofia","family":"Marques","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2562-8518","authenticated-orcid":false,"given":"Varadharajan","family":"Sundaramurthy","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-1041","authenticated-orcid":false,"given":"Maria M.","family":"Mota","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,11,19]]},"reference":[{"key":"1422_CR1","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1080\/15548627.2017.1378838","volume":"14","author":"L Yu","year":"2018","unstructured":"Yu, L., Chen, Y. & Tooze, S. 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