Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum.
Cryptosporidium parvum 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's eukaryotic initiation factor 4A (CpeIF4A; a DEAD-box RNA helica...
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Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012881 |
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| author | Meng Li Jigang Yin Dongqiang Wang Beibei Zou Guan Zhu |
| author_facet | Meng Li Jigang Yin Dongqiang Wang Beibei Zou Guan Zhu |
| author_sort | Meng Li |
| collection | DOAJ |
| description | Cryptosporidium parvum 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's 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-RNA-ATP complex with high affinity (Kd = 33.7 nM) and blocks protein synthesis in excysting sporozoites (IC50 ≈ 3.7 µM). In host-cell culture, Roc-A suppresses intracellular growth with nanomolar potency (EC50 = 1.77 nM) and a selectivity index exceeding 56,000 in HCT-8 cells and 1,400 in HepG2 cells. A five-day oral regimen (0.5 mg/kg/d) reduced oocyst shedding by >90% within 48 h in interferon-γ-knockout mice and by 70-90% 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. |
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| id | doaj-art-34b0f6e408564906960df8a0e398937e |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj-art-34b0f6e408564906960df8a0e398937e2025-08-20T03:02:27ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-07-01217e101288110.1371/journal.ppat.1012881Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum.Meng LiJigang YinDongqiang WangBeibei ZouGuan ZhuCryptosporidium parvum 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's 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-RNA-ATP complex with high affinity (Kd = 33.7 nM) and blocks protein synthesis in excysting sporozoites (IC50 ≈ 3.7 µM). In host-cell culture, Roc-A suppresses intracellular growth with nanomolar potency (EC50 = 1.77 nM) and a selectivity index exceeding 56,000 in HCT-8 cells and 1,400 in HepG2 cells. A five-day oral regimen (0.5 mg/kg/d) reduced oocyst shedding by >90% within 48 h in interferon-γ-knockout mice and by 70-90% 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.https://doi.org/10.1371/journal.ppat.1012881 |
| spellingShingle | Meng Li Jigang Yin Dongqiang Wang Beibei Zou Guan Zhu Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum. PLoS Pathogens |
| title | Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum. |
| title_full | Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum. |
| title_fullStr | Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum. |
| title_full_unstemmed | Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum. |
| title_short | Targeting translation initiation yields fast-killing therapeutics against the zoonotic parasite Cryptosporidium parvum. |
| title_sort | targeting translation initiation yields fast killing therapeutics against the zoonotic parasite cryptosporidium parvum |
| url | https://doi.org/10.1371/journal.ppat.1012881 |
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