{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T21:23:28Z","timestamp":1792531408869,"version":"4.5.0"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"11","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["DP2AI138239"],"award-info":[{"award-number":["DP2AI138239"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21-AI130406-01A1"],"award-info":[{"award-number":["R21-AI130406-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,3,17]]},"abstract":"<jats:p>\n                    The antihistamine clemastine inhibits multiple stages of the\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of clemastine and identify that clemastine binds to the\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    TCP-1 ring complex or chaperonin containing TCP-1 (TRiC\/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    TRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a clemastine-induced thermodynamic stabilization of the\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    TRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that clemastine reduces levels of the major TRiC substrate tubulin in\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    parasites. In addition, clemastine treatment leads to disorientation of\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    mitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species selectivity required for targeting an intracellular human pathogen. Our findings encourage larger efforts to apply chemoproteomic methods to assist in target identification of antimalarial drugs and highlight the potential to selectively target\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    TRiC-mediated protein folding for malaria intervention.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1913525117","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T16:44:32Z","timestamp":1583253872000},"page":"5810-5817","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["<i>Plasmodium<\/i>\n                    chaperonin TRiC\/CCT identified as a target of the antihistamine clemastine using parallel chemoproteomic strategy"],"prefix":"10.1073","volume":"117","author":[{"given":"Kuan-Yi","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27708;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiyi","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4570-7432","authenticated-orcid":false,"given":"Kayla","family":"Sylvester","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27708;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamanna","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-8844","authenticated-orcid":false,"given":"Emily R.","family":"Derbyshire","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27708;"},{"name":"Department of Chemistry, Duke University, Durham, NC 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