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Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2366-E2375. doi: 10.1073/pnas.1713000115. Epub 2018 Feb 20.

Rocaglates as dual-targeting agents for experimental cerebral malaria.

Author information

1
Department of Biochemistry, McGill University, Montreal, QC, H3G 0B1 Canada; david.langlais@mcgill.ca philippe.gros@mcgill.ca.
2
McGill University Research Center on Complex Traits, McGill University, Montreal, QC, H3G 0B1 Canada.
3
Department of Biochemistry, McGill University, Montreal, QC, H3G 0B1 Canada.
4
Department of Medicine, Toronto General Hospital-University Health Network, University of Toronto, Toronto, ON, M5G 2C4 Canada.
5
Department of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA 02215.
6
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2 Canada.

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 in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.

KEYWORDS:

Plasmodium; cerebral malaria; dual target; protein translation; severe malaria

PMID:
29463745
PMCID:
PMC5877959
DOI:
10.1073/pnas.1713000115
[Indexed for MEDLINE]
Free PMC Article

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