Selective modulation of plasmodial Hsp70s by small molecules with antimalarial activity

2014 ◽  
Vol 395 (11) ◽  
pp. 1353-1362 ◽  
Author(s):  
Ingrid L. Cockburn ◽  
Aileen Boshoff ◽  
Eva-Rachele Pesce ◽  
Gregory L. Blatch
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Small Molecules ◽  
Drug Targets ◽  
Antimalarial Activity ◽  
New Class ◽  
Mammalian Cell Lines ◽  
Marine Alkaloid ◽  
Selective Modulation ◽  
Human Hsp70

Abstract Plasmodial heat shock protein 70 (Hsp70) chaperones represent a promising new class of antimalarial drug targets because of the important roles they play in the survival and pathogenesis of the malaria parasite Plasmodium falciparum. This study assessed a set of small molecules (lapachol, bromo-β-lapachona and malonganenones A, B and C) as potential modulators of two biologically important plasmodial Hsp70s, the parasite-resident PfHsp70-1 and the exported PfHsp70-x. Compounds of interest were assessed for modulatory effects on the steady-state basal and heat shock protein 40 (Hsp40)-stimulated ATPase activities of PfHsp70-1, PfHsp70-x and human Hsp70, as well as on the protein aggregation suppression activity of PfHsp70-x. The antimalarial marine alkaloid malonganenone A was of particular interest, as it was found to have limited cytotoxicity to mammalian cell lines and exhibited the desired properties of an effective plasmodial Hsp70 modulator. This compound was found to inhibit plasmodial and not human Hsp70 ATPase activity (Hsp40-stimulated), and hindered the aggregation suppression activity of PfHsp70-x. Furthermore, malonganenone A was shown to disrupt the interaction between PfHsp70-x and Hsp40. This is the first report to show that PfHsp70-x has chaperone activity, is stimulated by Hsp40 and can be specifically modulated by small molecule compounds.

Induction of the heat shock response in Arabidopsis by heat shock protein 70 inhibitor VER-155008

2019 ◽  
Vol 46 (10) ◽  
pp. 925
Author(s):  
Erina Matsuoka ◽  
Naoki Kato ◽  
Masakazu Hara
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Response ◽  
Wheat Germ ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Wheat Germ Extract ◽  
Chlorophyll Contents ◽  
Shock Response ◽  
Human Hsp70

The heat shock protein 90 (HSP90) inhibitor, geldanamycin, is a chemical inducer of the heat shock response (HSR) in Arabidopsis. Geldanamycin is thought to activate the heat shock signal by dissociating the HSP90-heat shock factor (HSF) complex. Recent studies have indicated that plant HSP70 is also associated with HSF, suggesting that inhibition of HSP70 may induce the HSR. However, no studies have been conducted to test this hypothesis. Here, we found that a specific HSP70 inhibitor VER-155008 activated the promoter of a small HSP gene (At1 g53540, HSP17.6C-CI) of Arabidopsis, which was shown to be activated by geldanamycin and other HSP90 inhibitors. The production of HSP17.6C-CI, HSP70 and HSP90.1 proteins in Arabidopsis was enhanced by the addition of VER-155008. The reduction of chlorophyll contents by heat shock was ameliorated by VER-155008. Chaperone analyses indicated that VER-155008 inhibited the chaperone activities of wheat germ extract and human HSP70/HSP40, respectively. These results suggest that the inhibition of HSP70 by VER-155008 enhanced the heat tolerance of Arabidopsis by inducing the HSR in the plant.

scholarly journals Interaction of human heat shock protein 70 with tumor-associated peptides

2009 ◽  
Vol 390 (4) ◽  
Author(s):  
Maya J. Pandya ◽  
Henriette Bendz ◽  
Florian Manzenrieder ◽  
Elfriede Noessner ◽  
Horst Kessler ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
T Cell Activation ◽  
Heat Shock Protein 70 ◽  
Cell Activation ◽  
Peptide Sequence ◽  
Antigenic Peptides ◽  
Human Hsp70

Abstract Molecular chaperones of the heat shock protein 70 (Hsp70) family play a crucial role in the presentation of exogenous antigenic peptides by antigen-presenting cells (APCs). In a combined biochemical and immunological approach, we characterize the biochemical interaction of tumor-associated peptides with human Hsp70 and show that the strength of this interaction determines the efficacy of immunological cross-presentation of the antigenic sequences by APCs. A fluorescein-labeled cytosolic mammalian Hsc70 binding peptide is shown to interact with human Hsp70 molecules with high affinity (Kd=0.58 μm at 25°C). Competition experiments demonstrate weaker binding by Hsp70 of antigenic peptides derived from the tumor-associated proteins tyrosinase (Kd=32 μm) and melanoma antigen recognized by T cells (MART-1) (Kd=2.4 μm). Adding a peptide sequence (pep70) with high Hsp70 binding affinity (Kd=0.04 μm) to the tumor-associated peptides enables them to strongly interact with Hsp70. Presentation of tumor-associated peptides by B cells resulting in T cell activation in vitro is enhanced by Hsp70 when the tumor-associated peptides contain the Hsp70 binding sequence. This observation has relevance for vaccine design, as augmented transfer of tumor-associated antigens to APCs is closely linked to the vaccine's efficacy of T cell stimulation.

scholarly journals Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (Hsp90): Synthesis, biology, and molecular modeling

2008 ◽  
Vol 16 (14) ◽  
pp. 6903-6910 ◽  
Author(s):  
Thota Ganesh ◽  
Jaeki Min ◽  
Pahk Thepchatri ◽  
Yuhong Du ◽  
Lian Li ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
New Class

scholarly journals Heat Shock Protein 60 Acts as a Receptor for the Listeria Adhesion Protein in Caco-2 Cells

2004 ◽  
Vol 72 (2) ◽  
pp. 931-936 ◽  
Author(s):  
Jennifer L. Wampler ◽  
Kwang-Pyo Kim ◽  
Ziad Jaradat ◽  
Arun K. Bhunia
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Western Blot ◽  
Host Cell ◽  
Cell Receptor ◽  
Eukaryotic Cells ◽  
Heat Shock Protein 60 ◽  
Adhesion Protein ◽  
Host Cell Receptor ◽  
Mammalian Cell Lines

ABSTRACT The 104-kDa Listeria adhesion protein (LAP) in Listeria monocytogenes is involved in binding to various mammalian cell lines. However, the receptor that interacts with LAP in eukaryotic cells is unknown. In this study, scanning immunoelectron microscopy qualitatively demonstrated greater binding capacity of wild-type (WT) L. monocytogenes strain (F4244) than a LAP-deficient mutant strain (KB208) to Caco-2 cells. The goal of this study was identification of the host cell receptor for LAP. Using a Western blot ligand overlay assay, we identified a protein of 58 kDa to be the putative receptor for LAP from Caco-2 cells. N-terminal sequencing and subsequent database search identified this protein as heat shock protein 60 (Hsp60). Modified immunoseparation with protein A-Sepharose beads bound to the LAP-specific monoclonal antibody H7 (MAb-H7) and a sequential incubation with LAP preparation and Caco-2 lysate confirmed the receptor to be the same 58-kDa protein. Western blot analysis with anti-Hsp60 MAb of whole-cell adhesion between Caco-2 and WT also revealed the receptor protein to be a 58-kDa protein, thus corroborating the identification of Hsp60 as a host cell receptor for LAP. Furthermore, the anti-Hsp60 antibody also caused approximately 74% reduction in binding of L. monocytogenes WT to Caco-2 cells, whereas a control antibody, C11E9, had no effect on binding. The adhesion mechanism of L. monocytogenes to eukaryotic cells is a complex process, and identification of Hsp60 as a receptor for LAP adds to the list of previously discovered ligand-receptor modules that are essential to achieve successful adhesion.

Inhibition of Vesicular Stomatitis Virus Replication by Prostaglandin A1 in Aedes albopictus Cells

2004 ◽  
Vol 59 (1-2) ◽  
pp. 127-131 ◽  
Author(s):  
Fernanda M. Burlandy ◽  
Davis F. Ferreira ◽  
Moacyr A. Rebello
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Vesicular Stomatitis Virus ◽  
Aedes Albopictus ◽  
Virus Production ◽  
Immunoblot Analysis ◽  
Specific Protein ◽  
Mammalian Cell Lines ◽  
Vesicular Stomatitis ◽  
Prostaglandin A1

Cyclopentenone prostaglandins (PGs) exhibit antiviral activity against RNA and DNA viruses in mammalian cell lines, and this effect has been associated with the induction of a heat shock protein (hsp70). We investigated the effect of prostaglandin A1 (PGA1) on the replication of vesicular stomatitis virus (VSV) in Aedes albopictus (mosquito) cells. PGA1 was found to inhibit VSV replication dose dependently. Virus yield was reduced to 50% (3 μg PGA1/ml) and to 95% with 8 μg PGA1/ml. Even with the dramatic reduction of virus production observed in cells treated with PGA1, VSV-specific protein synthesis was unaltered. Treatment of cells with PGA1 (5 μg/ml) stimulated the synthesis of a polypeptide identified as a heat-shock protein (hsp) by immunoblot analysis. PGA1 induced hsp70 synthesis in uninfected cells. However, in VSV-infected cells the induction of hsp70 by PGA1 was reduced. This is the first report of antiviral effects of PGs affecting the replication of VSV in a mosquito cell line.

scholarly journals A chemical inhibitor of heat shock protein 78 (HSP78) from Leishmania donovani represents a potential antileishmanial drug candidate

2020 ◽  
Vol 295 (29) ◽  
pp. 9934-9947
Author(s):  
Sonali Das ◽  
Anindyajit Banerjee ◽  
Mohd Kamran ◽  
Sarfaraz Ahmad Ejazi ◽  
Mohammad Asad ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Amphotericin B ◽  
Drug Targets ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Mitogen Activated Protein Kinase ◽  
Drug Candidate ◽  
Disease Manifestation ◽  
Murine Bone Marrow

The emergence of resistance to available antileishmanial drugs advocates identification of new drug targets and their inhibitors for visceral leishmaniasis. Here, we identified Leishmania donovani heat shock protein 78 (LdHSP78), a putative caseinolytic protease, as important for parasite infection of host macrophages and a potential therapeutic target. Enrichment of LdHSP78 in infected humans, hamsters, and parasite amastigotes suggested its importance for disease persistence. Heterozygous knockouts of L. donovani HSP78 (LdHSP78+/−) and Leishmania mexicana HSP78 (LmxHSP78+/−) were generated using a flanking UTR-based multifragment ligation strategy and the CRISPR-Cas9 technique, respectively to investigate the significance of HSP78 for disease manifestation. The LdHSP78+/− parasite burden was dramatically reduced in both murine bone marrow-derived macrophages and hamsters, in association with enrichment of proinflammatory cytokines and NO. This finding implies that LdHSP78+/− parasites cannot suppress immune activation and escape NO-mediated toxicity in macrophages. Furthermore, phosphorylation of the mitogen-activated protein kinase p38 was enhanced and phosphorylation of extracellular signal-regulated kinase 1/2 was decreased in cells infected with LdHSP78+/− parasites, compared with WT parasites. Virulence of the LdHSP78+/− strain was restored by episomal addition of the LdHSP78 gene. Finally, using high-throughput virtual screening, we identified P1,P5-di(adenosine-5′)-pentaphosphate (Ap5A) ammonium salt as an LdHSP78 inhibitor. It selectively induced amastigote death at doses similar to amphotericin B doses, while exhibiting much less cytotoxicity to healthy macrophages than amphotericin B. In summary, using both a genetic knockout approach and pharmacological inhibition, we establish LdHSP78 as a drug target and Ap5A as a potential lead for improved antileishmanial agents.

Synthesis and Biological Activities of a New Class of Heat Shock Protein 90 Inhibitors, Designed by Energy-Based Pharmacophore Virtual Screening

2013 ◽  
Vol 56 (8) ◽  
pp. 3424-3428 ◽  
Author(s):  
Antonino Lauria ◽  
Ilenia Abbate ◽  
Carla Gentile ◽  
Francesca Angileri ◽  
Annamaria Martorana ◽  
...  
Keyword(s):  
Heat Shock ◽  
Virtual Screening ◽  
Heat Shock Protein ◽  
Biological Activities ◽  
Heat Shock Protein 90 ◽  
New Class
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