Rocaglates as dual-targeting agents for experimental cerebral malaria

Proceedings of the National Academy of Sciences of the United States of America
David LanglaisPhilippe Gros

Abstract

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response...Continue Reading

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Citations

Mar 12, 2021·Wiley Interdisciplinary Reviews. RNA·J J David HoPhilip A Marsden
Jun 13, 2020·Bioorganic & Medicinal Chemistry Letters·Huaisheng ZhangIfedayo Victor Ogungbe
Jun 10, 2021·Phytochemistry Reviews : Proceedings of the Phytochemical Society of Europe·Harald Greger
Oct 18, 2019·Journal of Natural Products·Garima AgarwalA Douglas Kinghorn

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