Evidence for the contribution of the hemozoin synthesis pathway of the murine Plasmodium yoelii to the resistance to artemisinin-related drugs.

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia.

Iron(II) binding to amyloid-ß, the Alzheimer's peptide.

Iron has been implicated in Alzheimer's disease, but until now no direct proof of Fe(II) binding to the amyloid-ß peptide (Aß) has been reported. We used NMR to evidence Fe(II) coordination to full-length Aß40 and truncated Aß16 peptides at physiological pH and to show that the Fe(II) binding site is located in the first 16 amino-acid residues. Fe(II) caused selective broadening of some NMR peaks that was dependent on the Fe:Aß stoichiometry and temperature. Analysis of Fe(II) broadening effect in the (1)H, (13)C, and 2D NMR data established that Asp1, Glu3, the three His, but not Tyr10 nor Met35 are the residues mainly involved in Fe(II) coordination.