Peptidyl inhibition of Spt4‐Spt5: Protein‐protein inhibitors for targeting the transcriptional pathway related to C9orf72 expansion repeats

2020 ◽  
Vol 121 (12) ◽  
pp. 4922-4930
Author(s):  
Alexey Rayevsky ◽  
Maxim Platonov ◽  
Vasyl Hurmach ◽  
Anastasia Yakovenko ◽  
Dmitriy Volochnyuk
Keyword(s):  
Protein Inhibitors ◽  
C9orf72 Expansion ◽  
Transcriptional Pathway

Trophoblastäre Funktionen werden durch Protein Inhibitors of Activated STATs (PIAS) reguliert

2009 ◽  
Vol 213 (02) ◽  
Author(s):  
L Khachaturyan ◽  
T Pöhlmann ◽  
M Weber ◽  
J Fitzgerald ◽  
E Schleußner ◽  
...  
Keyword(s):  
Protein Inhibitors

scholarly journals Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2138 ◽  
Author(s):  
Takumi Satoh ◽  
Stuart Lipton
Keyword(s):  
Side Effects ◽  
Specific Interaction ◽  
Dimethyl Fumarate ◽  
Carnosic Acid ◽  
European Medicines Agency ◽  
Related Factor ◽  
Inflammatory Phase ◽  
First Case ◽  
Systemic Side Effects ◽  
Transcriptional Pathway

Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera®. It was approved in 2013 by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF is stimulation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional pathway that induces anti-oxidant and anti-inflammatory phase II enzymes to prevent chronic neurodegeneration. However, electrophiles such as DMF also produce severe systemic side effects, in part due to non-specific S-alkylation of cysteine thiols and resulting depletion of glutathione. This mini-review presents the present status and future strategy for NRF2 activators designed to avoid these side effects. Two modes of chemical reaction leading to NRF2 activation are considered here. The first mode is S-alkylation (covalent reaction) of thiols in Kelch-like ECH-associated protein 1 (KEAP1), which interacts with NRF2. The second mechanism involves non-covalent pharmacological inhibition of protein-protein interactions, in particular domain-specific interaction between NRF2 and KEAP1 or other repressor proteins involved in this transcriptional pathway. There have been significant advances in drug development using both of these mechanisms that can potentially avoid the systemic side effects of electrophilic compounds. In the first case concerning covalent reaction with KEAP1, monomethyl fumarate and monoethyl fumarate appear to represent safer derivatives of DMF. In a second approach, pro-electrophilic drugs, such as carnosic acid from the herb Rosmarinus officinalis, can be used as a safe pro-drug of an electrophilic compound. Concerning non-covalent activation of NRF2, drugs are being developed that interfere with the direct interaction of KEAP1-NRF2 or inhibit BTB domain and CNC homolog 1 (BACH1), which is a transcriptional repressor of the promoter where NRF2 binds.

The Only Function of Grauzone Required for Drosophila Oocyte Meiosis Is Transcriptional Activation of the cortex Gene

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1831-1839
Author(s):  
Emily Harms ◽  
Tehyen Chu ◽  
Gwénola Henrion ◽  
Sidney Strickland
Keyword(s):  
Zinc Finger ◽  
Transcriptional Activation ◽  
Single Amino Acid ◽  
Primary Role ◽  
Extra Copy ◽  
Oocyte Meiosis ◽  
Zinc Finger Motifs ◽  
High Level ◽  
Transcriptional Pathway

Abstract The grauzone and cortex genes are required for the completion of meiosis in Drosophila oocytes. The grauzone gene encodes a C2H2-type zinc-finger transcription factor that binds to the cortex promoter and is necessary for high-level activation of cortex transcription. Here we define the region of the cortex promoter to which Grauzone binds and show that the binding occurs through the C-terminal, zinc-finger-rich region of the protein. Mutations in two out of the five grauzone alleles result in single amino acid changes within different zinc-finger motifs. Both of these mutations result in the inability of Grauzone to bind DNA effectively. To determine the mechanism by which Grauzone regulates meiosis, transgenic flies were produced with an extra copy of the cortex gene in homozygous grauzone females. This transgene rescued the meiosis arrest of embryos from these mutants and allowed their complete development, indicating that activation of cortex transcription is the primary role of Grauzone during Drosophila oogenesis. These experiments further define a new transcriptional pathway that controls the meiotic cell cycle in Drosophila oocytes.

MITOGEN-ACTIVATED PROTEIN INHIBITORS

2019 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Michel van Lint ◽  
Herlinde Ebraert ◽  
Elisabeth H. Van Aken
Keyword(s):  
Protein Inhibitors ◽  
Mitogen Activated Protein

C9orf72 expansion as a possible genetic cause of Huntington disease phenocopy syndrome

2014 ◽  
Vol 261 (10) ◽  
pp. 1917-1921 ◽  
Author(s):  
Vladimir S. Kostić ◽  
Valerija Dobričić ◽  
Iva Stanković ◽  
Vesna Ralić ◽  
Elka Stefanova
Keyword(s):  
Huntington Disease ◽  
C9orf72 Expansion
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