Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1
-
Ingrid L. Cockburn
Abstract
Plasmodium falciparum heat shock protein 70 (PfHsp70-1) is thought to play an essential role in parasite survival and virulence in the human host, making it a potential antimalarial drug target. A malate dehydrogenase based aggregation suppression assay was adapted for the screening of small molecule modulators of Hsp70. A number of small molecules of natural (marine prenylated alkaloids and terrestrial plant naphthoquinones) and related synthetic origin were screened for their effects on the protein aggregation suppression activity of purified recombinant PfHsp70-1. Five compounds (malonganenone A-C, lapachol and bromo-β-lapachona) were found to inhibit the chaperone activity of PfHsp70-1 in a concentration dependent manner, with lapachol preferentially inhibiting PfHsp70-1 compared to another control Hsp70. Using growth inhibition assays on P. falciparum infected erythrocytes, all of the compounds, except for malonganenone B, were found to inhibit parasite growth with IC50 values in the low micromolar range. Overall, this study has identified two novel classes of small molecule inhibitors of PfHsp70-1, one representing a new class of antiplasmodial compounds (malonganenones). In addition to demonstrating the validity of PfHsp70-1 as a possible drug target, the compounds reported in this study will be potentially useful as molecular probes for fundamental studies on Hsp70 chaperone function.
©2011 by Walter de Gruyter Berlin New York
Articles in the same Issue
- Review
- Recent insights into regulation of transcription by RNA polymerase III and the cellular functions of its transcripts
- Genes and Nucleic Acids
- Post-transcriptional regulation of human cathepsin L expression
- Protein Structure and Function
- In vitro conversion and seeded fibrillization of posttranslationally modified prion protein
- Synthesis of recombinant high density lipoprotein with apolipoprotein A-I and apolipoprotein A-V
- Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1
- Molecular Medicine
- Inhibition of AP-1 suppresses cervical cancer cell proliferation and is associated with p21 expression
- STAT3 controls matrix metalloproteinase-1 expression in colon carcinoma cells by both direct and AP-1-mediated interaction with the MMP-1 promoter
- Cell Biology and Signaling
- TGFβ1 suppresses vascular smooth muscle cell motility by expression of N-cadherin
- Renal pro-apoptotic proteins are reduced by growth hormone resistance but not by visceral fat removal
- Proteolysis
- Inhibition of Staphylococcus aureus cysteine proteases by human serpin potentially limits staphylococcal virulence
Articles in the same Issue
- Review
- Recent insights into regulation of transcription by RNA polymerase III and the cellular functions of its transcripts
- Genes and Nucleic Acids
- Post-transcriptional regulation of human cathepsin L expression
- Protein Structure and Function
- In vitro conversion and seeded fibrillization of posttranslationally modified prion protein
- Synthesis of recombinant high density lipoprotein with apolipoprotein A-I and apolipoprotein A-V
- Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1
- Molecular Medicine
- Inhibition of AP-1 suppresses cervical cancer cell proliferation and is associated with p21 expression
- STAT3 controls matrix metalloproteinase-1 expression in colon carcinoma cells by both direct and AP-1-mediated interaction with the MMP-1 promoter
- Cell Biology and Signaling
- TGFβ1 suppresses vascular smooth muscle cell motility by expression of N-cadherin
- Renal pro-apoptotic proteins are reduced by growth hormone resistance but not by visceral fat removal
- Proteolysis
- Inhibition of Staphylococcus aureus cysteine proteases by human serpin potentially limits staphylococcal virulence
