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

Abstract

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.

CONCLUSION:

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.

• Authors: Jennifer M Reynolds, Kamal El Bissati, Jens Brandenburg, Arthur Günzl, Choukri Ben Mamoun
• Journal: BMC clinical pharmacology (BMC Clin Pharmacol) Vol. 7 Pg. 13 (Oct 23 2007) ISSN: 1472-6904 [Electronic] England
• PMID: 17956613 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antimalarials
• Antineoplastic Agents
• Boron Compounds
• Boronic Acids
• Oligopeptides
• Protease Inhibitors
• Proteasome Inhibitors
• Pyrazines
• benzyloxycarbonyl-leucyl-leucyl-leucylboronate
• Bortezomib

Topics

• Animals
• Antimalarials (pharmacology)
• Antineoplastic Agents (pharmacology)
• Boron Compounds (pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• DNA Replication (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance
• Erythrocytes (drug effects, parasitology)
• Inhibitory Concentration 50
• Life Cycle Stages (drug effects)
• Oligopeptides (pharmacology)
• Plasmodium falciparum (drug effects, growth & development)
• Protease Inhibitors (pharmacology)
• Proteasome Inhibitors
• Pyrazines (pharmacology)