Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B

Proteasome inhibitor bortezomib (Velcade？: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid), which has been approved for treatment of patients with multiple myeloma, and a second boronate analog Z-Leu-Leu-Leu-B(OH)2 (ZL3B), were tested against four different strains of P. falciparum (3D7, HB3, W2 and Dd2) that are either sensitive or have different levels of resistance to the antimalarial drugs pyrimethamine and chloroquine.Bortezomib and ZL3B are equally effective against drug-sensitive and -resistant parasites and block intraerythrocytic development prior to DNA synthesis, but have no effect on parasite egress or invasion.The identification of bortezomib and its analog as potent antimalarial drugs will set the stage for the advancement of this class of compounds, either alone or in combination therapy, for treatment of malaria, and emphasize the need for large-scale screens to identify new antimalarials within the library of clinically approved compounds.Malaria is caused by intraerythrocytic protozoan parasites of the genus Plasmodium. It is responsible for more than 300 million clinical cases and over 2 million deaths annually [1]. Plasmodium falciparum, the organism that causes the most lethal form of the disease, is becoming increasingly resistant to almost all available drugs in the antimalarial armamentarium [1]. New chemotherapeutic strategies are therefore urgently needed to combat this disease.During its intraerythrocytic life cycle, a single P. falciparum parasite undergoes multiple morphological and physiological changes and multiplies to produce up to 36 new daughter parasites in ~48 hours. Large-scale genomic and proteomic analyses revealed a coordinated program of gene and protein expression during parasite intraerythrocytic life cycle [2-7]. The first phase of this program occurs during parasite transition from ring to trophzoite stage and is marked by the induction of expression of enzymes requir