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Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all <jats:italic>Plasmodium<\/jats:italic> stages, as a hitherto unexplored drug target in the pathogen.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Attempts to exacerbate the <jats:italic>P. falciparum<\/jats:italic> proteome\u2019s propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen\u2019s viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC<jats:sub>50<\/jats:sub> of 90\u00a0nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of <jats:italic>Plasmodium<\/jats:italic>. At its IC<jats:sub>50<\/jats:sub>, this compound is a powerful inhibitor of the aggregation of the model amyloid \u03b2 peptide fragment 1-40, and it reduces the amount of aggregated proteins in <jats:italic>P. falciparum<\/jats:italic> cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the <jats:italic>Plasmodium<\/jats:italic> cytosol, it is a theranostic agent.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Inhibiting protein aggregation in <jats:italic>Plasmodium<\/jats:italic> significantly reduces the parasite\u2019s viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12915-022-01374-4","type":"journal-article","created":{"date-parts":[[2022,10,22]],"date-time":"2022-10-22T00:03:10Z","timestamp":1666396990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures"],"prefix":"10.1186","volume":"20","author":[{"given":"In\u00e9s","family":"Bouz\u00f3n-Arn\u00e1iz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunuen","family":"Avalos-Padilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnau","family":"Biosca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Ca\u00f1o-Prades","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Rom\u00e1n-\u00c1lamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Andreu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Moita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Prud\u00eancio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa M.","family":"Arce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Mu\u00f1oz-Torrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-9631","authenticated-orcid":false,"given":"Xavier","family":"Fern\u00e0ndez-Busquets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,22]]},"reference":[{"key":"1374_CR1","doi-asserted-by":"crossref","unstructured":"Pallar\u00e8s I, de Groot NS, Iglesias V, Sant\u2019Anna R, Biosca A, Fern\u00e0ndez-Busquets X, et al. 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Blood was not collected specifically for this research; the purchased units had been discarded for transfusion, usually because of an excess of blood relative to anticoagulant solution. Prior to their use, blood units underwent the analytical checks specified in the current legislation. Before being delivered to us, unit data were anonymized and irreversibly dissociated, and any identification tag or label had been removed in order to guarantee the non-identification of the blood donor. No blood data were or will be supplied, in accordance with the current Spanish <i>Ley Org\u00e1nica de Protecci\u00f3n de Datos<\/i> and <i>Ley de Investigaci\u00f3n Biom\u00e9dica<\/i>. The blood samples will not be used for studies other than those made explicit in this research.For in vivo assays, in the presence of toxic effects including, among others,\u2009>\u200920% reduction in weight, aggressive and unexpected animal behavior or the presence of blood in feces, animals were immediately anesthetized using a 100\u00a0mg\/kg ketamine plus 10\u00a0mg\/kg xylazine mixture and sacrificed by cervical dislocation. The PCB animal facility has the relevant authorizations as approved establishment of breeding, supplier, and user (B9900044 and REGA code: ES080190036527) to work with vertebrate animals used for experimental and scientific purposes. The animal care and use protocols followed adhered to the specific national and international guidelines in accordance with the current Catalan (D 214\/1997\/GC) and Spanish laws (RD 53\/2013; order ECC\/566\/2015) and the corresponding European Directive (2010\/63 EU).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A patent application (EP21382949.2) has been filed to protect some of the results presented in the paper, which includes as inventors IB-A, AB, DM-T, and XF-B. All other authors declare they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"197"}}