{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:10:24Z","timestamp":1790824224636,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012881","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000}}],"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National key research and development, China","award":["2023YFD1801005"],"award-info":[{"award-number":["2023YFD1801005"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic><jats:italic>Cryptosporidium parvum<\/jats:italic><\/jats:italic> is a zoonotic apicomplexan that causes moderate-to-severe watery diarrhea in children, immunocompromised patients, and neonatal ruminants, yet no fully effective drug is available. We show that the parasite\u2019s eukaryotic initiation factor 4A (CpeIF4A; a DEAD-box RNA helicase in the eIF4F translation-initiation complex) can be exploited as a fast-killing therapeutic target. Rocaglamide A (Roc-A), a plant-derived rocaglate, binds the CpeIF4A\u2013RNA\u2013ATP complex with high affinity (K<jats:sub>d<\/jats:sub>\u2009=\u200933.7\u2009nM) and blocks protein synthesis in excysting sporozoites (IC<jats:sub>50<\/jats:sub>\u2009\u2248\u20093.7 \u00b5M). In host-cell culture, Roc-A suppresses intracellular growth with nanomolar potency (EC<jats:sub>50<\/jats:sub>\u2009=\u20091.77\u2009nM) and a selectivity index exceeding 56,000 in HCT-8 cells and 1,400 in HepG2 cells. A five-day oral regimen (0.5\u2009mg\/kg\/d) reduced oocyst shedding by &gt;90% within 48\u2009h in interferon-\u03b3\u2013knockout mice and by 70\u201390% from day 2 onward without rebound during a 15-day follow-up in NCG mice. Two amino-acid differences at the Roc-A binding surface (D165 and V192 in CpeIF4A vs. N167 and D194 in the human ortholog) offer a foothold for medicinal optimization toward greater parasite selectivity. These findings establish translation initiation as an unexplored but tractable pathway for anti-cryptosporidial drug discovery and position Roc-A as a promising lead compound.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012881","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T17:54:02Z","timestamp":1753725242000},"page":"e1012881","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum"],"prefix":"10.1371","volume":"21","author":[{"given":"Meng","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jigang","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0659","authenticated-orcid":true,"given":"Guan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"ppat.1012881.ref001","first-page":"1099","article-title":"Taxonomy and molecular epidemiology of Cryptosporidium and Giardia - a 50 year perspective (1971-2021","volume":"51","author":"UM Ryan","year":"2021","journal-title":"). 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