scholarly journals Crossing of the Cystic Barriers of Toxoplasma gondii by the Fluorescent Coumarin Tetra-Cyclopeptide

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7506
Author(s):  
Céline Dard ◽  
Baptiste Leforestier ◽  
Flaviane Francisco Hilário ◽  
Mohamed Dit Mady Traoré ◽  
Marie-Ange Lespinasse ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Cell Permeability ◽  
Apicomplexan Parasites ◽  
Inhibition Effect ◽  
Deacetylase Inhibitor ◽  
Penetration Mechanism ◽  
Cyclic Tetrapeptide

FR235222 is a natural tetra-cyclopeptide with a strong inhibition effect on histone deacetylases, effective on mammalian cells as well as on intracellular apicomplexan parasites, such as Toxoplasma gondii, in the tachyzoite and bradyzoite stages. This molecule is characterized by two parts: the zinc-binding group, responsible for the binding to the histone deacetylase, and the cyclic tetrapeptide moiety, which plays a crucial role in cell permeability. Recently, we have shown that the cyclic tetrapeptide coupled with a fluorescent diethyl-amino-coumarin was able to maintain properties of cellular penetration on human cells. Here, we show that this property can be extended to the crossing of the Toxoplasma gondii cystic cell wall and the cell membrane of the parasite in its bradyzoite form, while maintaining a high efficacy as a histone deacetylase inhibitor. The investigation by molecular modeling allows a better understanding of the penetration mechanism.

scholarly journals A Tiny Change Makes a Big Difference in the Anti-Parasitic Activities of an HDAC Inhibitor

2019 ◽  
Vol 20 (12) ◽  
pp. 2973 ◽  
Author(s):  
Corinne Loeuillet ◽  
Bastien Touquet ◽  
Jean François Guichou ◽  
Gilles Labesse ◽  
Denis Sereno
Keyword(s):  
Toxoplasma Gondii ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
In Silico ◽  
Histone Deacetylase Inhibitor ◽  
Type Ii ◽  
Deacetylase Inhibitor ◽  
In Silico Modeling ◽  
High Conservation ◽  
Methyl Benzene

We previously synthesized an hydroxamate derivative (N-hydroxy-4-[2-(3- methoxyphenyl)acetamido]benzamide) named 363 with potent anti-Toxoplasma gondii activity and histone deacetylase inhibitor (HDACi) effects. Here we show that 1-N-hydroxy-4-N- [(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide, a 363 isomer, does not have antiparasitic potency and has a 13-fold decrease in HDACi activity. The in silico modeling of T. gondii HDACs of the type II strain discloses identity varying from 25% to 62% on more than 250 residues for S8EP32_TOXG and A0A125YPH4_TOXGM. We observed a high conservation degree with the human HDAC2 (53% and 64% identity, respectively) and a moderate one with the human HDAC8 (30–40%). Two other TgHDACs, S8F6L4_TOXGM and S8GEI3_TOXGM, were identified as displaying a higher similarity with some bacterial orthologs (~35%) than with the human enzymes (~25%). The docking in parallel of the two compounds on the models generated allowed us to gain insights on the docking of these hydroxamate derivatives that guide their specificity and potency against T. gondii histone deacetylase. This information would constitute the rationale from which more specific derivatives can be synthetized.

scholarly journals Autoregulation of Mouse Histone Deacetylase 1 Expression

2003 ◽  
Vol 23 (19) ◽  
pp. 6993-7004 ◽  
Author(s):  
Bernd Schuettengruber ◽  
Elisabeth Simboeck ◽  
Harald Khier ◽  
Christian Seiser
Keyword(s):  
Histone Deacetylase ◽  
Binding Sites ◽  
Mammalian Cells ◽  
Promoter Activity ◽  
Cell Cycle Progression ◽  
Trichostatin A ◽  
Consensus Sequence ◽  
Histone Deacetylase 1 ◽  
Deacetylase Inhibitor ◽  
Ccaat Box

ABSTRACT Histone deacetylase 1 (HDAC1) is a major regulator of chromatin structure and gene expression. Tight control of HDAC1 expression is essential for development and normal cell cycle progression. In this report, we analyzed the regulation of the mouse HDAC1 gene by deacetylases and acetyltransferases. The murine HDAC1 promoter lacks a TATA box consensus sequence but contains several putative SP1 binding sites and a CCAAT box, which is recognized by the transcription factor NF-Y. HDAC1 promoter-reporter studies revealed that the distal SP1 site and the CCAAT box are crucial for HDAC1 promoter activity and act synergistically to constitute HDAC1 promoter activity. Furthermore, these sites are essential for activation of the HDAC1 promoter by the deacetylase inhibitor trichostatin A (TSA). Chromatin immunoprecipitation assays showed that HDAC1 is recruited to the promoter by SP1 and NF-Y, thereby regulating its own expression. Coexpression of acetyltransferases elevates HDAC1 promoter activity when the SP1 site and the CCAAT box are intact. Increased histone acetylation at the HDAC1 promoter region in response to TSA treatment is dependent on binding sites for SP1 and NF-Y. Taken together, our results demonstrate for the first time the autoregulation of a histone-modifying enzyme in mammalian cells.

scholarly journals Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression

2000 ◽  
Vol 14 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Hung-Ying Kao ◽  
Michael Downes ◽  
Peter Ordentlich ◽  
Ronald M. Evans
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Class Ii ◽  
Class I ◽  
Nuclear Compartment ◽  
New Family ◽  
Repressive Effect ◽  
Two Hybrid

The transcriptional corepressor SMRT functions by mediating the repressive effect of transcription factors involved in diverse signaling pathways. The mechanism by which SMRT represses basal transcription has been proposed to involve the indirect recruitment of histone deacetylase HDAC1 via the adaptor mSin3A. In contrast to this model, a two-hybrid screen on SMRT-interacting proteins resulted in the isolation of the recently described HDAC5 and a new family member termed HDAC7. Molecular and biochemical results indicate that this interaction is direct and in vivo evidence colocalizes SMRT, mHDAC5, and mHDAC7 to a distinct nuclear compartment. Surprisingly, HDAC7 can interact with mSin3A in yeast and in mammalian cells, suggesting association of multiple repression complexes. Taken together, our results provide the first evidence that SMRT-mediated repression is promoted by class I and class II histone deacetylases and that SMRT can recruit class II histone deacetylases in a mSin3A-independent fashion.

scholarly journals Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells

AIDS ◽  
2013 ◽  
Vol 27 (18) ◽  
pp. 2853-2862 ◽  
Author(s):  
Fiona Wightman ◽  
Hao K. Lu ◽  
Ajantha E. Solomon ◽  
Suha Saleh ◽  
Andrew N. Harman ◽  
...  
Keyword(s):  
T Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Histone Deacetylases ◽  
Deacetylase Inhibitor ◽  
Class 1 ◽  
Latently Infected

scholarly journals Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues

2008 ◽  
Vol 52 (4) ◽  
pp. 1454-1461 ◽  
Author(s):  
K. T. Andrews ◽  
T. N. Tran ◽  
A. J. Lucke ◽  
P. Kahnberg ◽  
G. T. Le ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mammalian Cells ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Hdac Inhibition ◽  
Deacetylase Inhibitor ◽  
New Compounds ◽  
Late Stages

ABSTRACT The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.

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