RNA helicases are molecular motors that are involved in virtually all aspects of RNA metabolism. Eukaryotic initiation factor (eIF) 4A is the prototypical member of the DEAD-box family of RNA helicases. It is thought to use energy from ATP hydrolysis to unwind mRNA structure and, in conjunction with other translation factors, it prepares mRNA templates for ribosome recruitment during translation initiation. In screening marine extracts for new eukaryotic translation initiation inhibitors, we identified the natural product hippuristanol. We show here that this compound is a selective and potent inhibitor of eIF4A RNA-binding activity that can be used to distinguish between eIF4A-dependent and -independent modes of translation initiation in vitro and in vivo. We also show that poliovirus replication is delayed when infected cells are exposed to hippuristanol. Our study demonstrates the feasibility of selectively targeting members of the DEAD-box helicase family with small-molecule inhibitors.

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Manzamine A, a ␤-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasite Plasmodium berghei in vivo. More than 90% of the asexual erythrocytic stages of P. berghei were inhibited after a single intraperitoneal injection of manzamine A into infected mice. A remarkable aspect of manzamine A treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. Oral administration of an oil suspension of manzamine A also produced significant reductions in parasitemia. The plasma manzamine A concentration peaked 4 h after injection and remained high even at 48 h. Morphological changes of P. berghei were observed 1 h after treatment of infected mice. (؊)-8-Hydroxymanzamine A also displayed antimalarial activity, whereas manzamine F, a ketone analog of manzamine A, did not. Our results suggest that manzamine A and (؊)-8-hydroxymanzamine A are promising new antimalarial agents.Malaria remains the most devastating infectious parasitic disease, inflicting both death and economic losses on at least half the world's population. Numerous attempts have been made to control the disease by using vector control measures and/or chemoprophylaxis, but they have had limited success (18). Immunoprophylaxis holds promise, but effective vaccines are still not available. Presently, the most effective way of dealing with malaria is the administration of chemotherapeutic agents. Although drug treatments of malaria are currently the best means of disease management, there is an urgent need for the development of structurally novel and effective antimalarial drugs because of increasing resistance to most presently available antimalarial drugs (15,16,19).Some of the most effective antimalarial drugs available, quinine and artemisinin, are natural products derived from terrestrial plants. However, recent research suggests that marine organisms may also produce compounds with activity against malaria parasites (4,11,21). Manzamines are a structurally unique group of ␤-carboline alkaloids isolated from several marine sponge species found in waters of the Indian Ocean and the Pacific Ocean. Manzamine A (Fig. 1) was initially isolated from a Haliclona sp. (17) but has been subsequently found in other genera of marine sponges, including Pellina (14), Pachypellina (7), Xestospongia (3, 8), Ircinia (10), and Amphimedon (9). In addition, more than 30 other compounds structurally related to manzamine A have been isolated from sponges and characterized; these include 8-hydroxymanzamine A and the ketone derivative manzamine F (Fig. 1). The origin, isolation, and chemistry of various manzamines have been reviewed (6, 13), with the complete synthesis of manzamine A being recently reported (20). The manzamines previously received considerable interest because of their potential as anticancer agents, with both manzamine A and manzamine F inhibiting the growth of P-388 mouse leukemia cells (6) and 8-hydroxymanzamine A showing moderate cytotoxici...

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