Rocaglates as dual-targeting agents for experimental cerebral malaria

Abstract

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

Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

“…Here, we report that targeting translation initiation may provide a strategy to combat this emerging pathogen. The rocaglates have shown activity against various xenograft tumors in mice (59) and in mouse models of malaria (64), indicating that the scaffold's whole-animal pharmacology is compatible with systemic treatment applications. To fully exploit rocaglates for the treatment of fungal infections, however, development of a more extensively fungus-selective analogue to avoid host toxicity in the context of acute fungal infections will likely be required.…”

Targeting the DEAD-Box RNA Helicase eIF4A with Rocaglates—A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

“…It is worth pointing out here that beyond their antiviral and antitumor activity, rocaglates have also been shown to have eIF4A-dependent antiplasmodial effects in vitro and in vivo against Plasmodium falciparum and P. berghei [ 135 ] and an eIF4A-dependent antifungal effect in vitro against Candida auris [ 136 ], further highlighting the broad therapeutic potential of this class of eIF4A-targeting compounds against potential pathogens.…”

Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP

“…Rocaglates are a class of natural compounds extracted from Aglaia genus that possess potent anti-neoplastic properties by targeting Targeting eIF4A using rocaglate CR-1-31B sensitizes gallbladder cancer cells to TRAIL-mediated apoptosis through the translational downregulation of c-FLIP eukaryotic translation initiation factor 4A (eIF4A) (9,10). In particular, CR-1-31B (CR-31), is a synthetic rocaglate, which has been shown to exhibit powerful inhibitory effects over eIF4A by perturbing the interaction between eIF4A and RNA, sequentially impeding initiation during protein synthesis (11). However, the exact anticancer effects of rocaglate CR-31 in GBC remain to be determined.…”