Rocaglates as dual-targeting agents for experimental cerebral malaria.

Abstract

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by <i>Plasmodium</i> 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 <i>Plasmodium</i> parasites. Rocaglates are a class of natural products derived from plants of the <i>Aglaia</i> 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 <i>Plasmodium falciparum</i> eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with <i>Plasmodium berghei</i> (CM) and <i>Plasmodium chabaudi</i> (blood-stage malaria), and can also block replication of different clinical isolates of <i>P. falciparum</i> in human erythrocytes infected ex vivo<i>,</i> including drug-resistant <i>P. falciparum</i> isolates. In vivo, a single dosing of CR-1-31B in <i>P. berghei</i>-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 <i>P. berghei</i>-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.