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

Jennifer M Reynolds,Kamal El Bissati,Choukri Ben Mamoun,Jens Brandenburg,Arthur Günzl

doi:10.1186/1472-6904-7-13

Jennifer M Reynolds, Kamal El Bissati + Show 3 more

Open Access

https://doi.org/10.1186/1472-6904-7-13

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Abstract

BackgroundThe 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.MethodsProteasome 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.ResultsBortezomib 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.ConclusionThe 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.

Highlights

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
ZL3B and bortezomib inhibit the P. falciparum intraerythrocytic cycle The cell permeable peptide boronate Z-Leu-Leu-LeuB(OH)2 (ZL3B) (Fig. 1A) is a specific and potent proteasome inhibitor that blocks the growth of the bloodstream form of the protozoan parasite Trypanosoma brucei with a 50% inhibitory concentration (IC50) of 0.32 nM in culture [14]
In order to examine the antimalarial activity of ZL3B, we have tested the effect of increasing concentrations of this compound up to 200 nM on the intraerythrocytic life cycle of P. falciparum in culture by following the incorporation of radiolabeled hypoxanthine into parasite nucleic acids

Summary

Introduction

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. 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]. 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 required for biosynthesis of proteins and membranes, nutrient acquisition, and degradation of the host cytoplasm. The rise and fall of expression of subsets of proteins during specific stages of parasite intraerythrocytic life cycle suggest a coordinated control of protein turnover during parasite development. In eukaryotes, such regulation is controlled by the proteasome

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