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PMID: 14514358 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin.

Malaria journal ·Vol. 2 ·2003-09-15 ·Pages 30

Kumar R, Musiyenko A, Barik S

Abstract

The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA), is a specific inhibitor of heat shock protein 90 (Hsp90) and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ) under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively) and on all erythrocytic stages of the parasite. Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Antimalarials/metabolism,pharmacology Benzoquinones Chloroquine/metabolism Cloning, Molecular Drug Resistance/physiology Drug Synergism Gene Expression Regulation, Developmental/drug effects,genetics HSP90 Heat-Shock Proteins/antagonists & inhibitors,genetics,metabolism Lactams, Macrocyclic Plasmodium falciparum/drug effects,genetics,growth & development,physiology Protozoan Proteins/antagonists & inhibitors,genetics,metabolism Quinones/metabolism,pharmacology
Chemicals
Antimalarials Benzoquinones HSP90 Heat-Shock Proteins Lactams, Macrocyclic Protozoan Proteins Quinones Chloroquine Adenosine Triphosphate geldanamycin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Kumar Rajinder
Department of Biochemistry and Molecular Biology (MSB 2370), University of South Alabama, College of Medicine, 307 University Blvd, Mobile, AL 36688-0002, USA. rkumar@usouthal.edu
Musiyenko Alla
Barik Sailen
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Article Info
Journal
Malaria journal
Abbr.
Malar J
ISSN
1475-2875
DOI
10.1186/1475-2875-2-30
Email
rkumar@usouthal.edu
Published
2003-09-15
Epub
2003-00-15
Pages
30
Language
English
Region
England
NLM ID
101139802
PMCID
PMC201030
Subset
IM
Grants
NIAID NIH HHS · R01 AI045803 · United States
NIAID NIH HHS · AI45803 · United States
External Links
PubMed source DOI: 10.1186/1475-2875-2-30 PMC Full Text View journal details
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