Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B.
BACKGROUND
The high rate of mortality due to malaria and the worldwide distribution of parasite resistance to the commonly used antimalarial drugs chloroquine and pyrimethamine emphasize the urgent need for the development of new antimalarial drugs. An alternative approach to the long and uncertain process of designing and developing new compounds is to identify among the armamentarium of drugs already approved for clinical treatment of various human diseases those that may have strong antimalarial activity.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Reynolds
Jennifer M
JM
Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-3301, USA. jreynolds@student.uchc.edu
El Bissati
Kamal
K
Brandenburg
Jens
J
Günzl
Arthur
A
Mamoun
Choukri Ben
CB
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001896:Boron Compounds / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*
D000962:Antimalarials; D000970:Antineoplastic Agents; D001896:Boron Compounds; D001897:Boronic Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; C117531:benzyloxycarbonyl-leucyl-leucyl-leucylboronate; D000069286:Bortezomib