DEKKER40

Novel approaches towards understanding of gene transcription using small molecules as tools

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 Obiettivo del progetto (Objective)

'Small molecule modulators of protein function proved to be effective tools to elucidate the functions of newly identified proteins in reverse chemical genetic studies. In the field of gene transcription regulation many new proteins with a poorly defined function are being discovered. Among these proteins many enzymes are found that modulate acylation and phosphorylation. These posttranslational modifications play an important role in cellular localization and protein-protein interactions of transcription factors. An interesting feature is that acylation competes with other posttranslational modification such as ubiquitinylation, sumoylation, palmitoylation etc. Acetylation can thus be considered a key regulatory event. We propose to develop small molecule inhibitors to study lysine acetyl transferases in a reverse chemical genetics approach. Furthermore, we propose to develop innovative chemical cross-linkers to specifically cross link lysine acetyl transferases and their targets in vivo in order to elucidate the binding partners of these enzymes. Together these small molecules will provide tools to study spatial and temporal control in gene transcription by the Smad transcription factors in fluorescence microscopy studies of cell based systems'

Introduzione (Teaser)

After a gene has been transcribed into a protein, many chemical events can occur that affect the structure and function of the molecule. As addition of small groups to the original molecule has a key regulatory role, the enzymes responsible are an excellent source of new drugs.

Descrizione progetto (Article)

The study of exactly what a gene does in terms of production of proteins (gene transcription) is providing many molecules for which the function is unknown. Among these are many enzymes that control the addition of small groups of atoms to newly transcribed proteins.

The EU-funded 'Novel approaches towards understanding of gene transcription using small molecules as tools' (Dekker40) project studied the phenomenon of post-translational modification using small molecule inhibitors. These prevent modification from taking place, allowing the exact role of the enzyme in question to then be determined.

One group of molecules of interest to the team in particular are histone acetyltransferases (HATs). These are a recently discovered group of enzymes for which there were no selective inhibitors to identify their function.

Two HAT enzymes were studied and the Dekker40 researchers identified several inhibitors for both molecules. This development will prove beneficial for so-called activity-based profiling where inhibitors are used as probes in different tissues to pinpoint active enzymes.

Inhibitors were also identified with improved potency in cell-based studies of histone acetylation. Inhibitors for HATs based on the natural product anacardic acid found in cashew nuts and mangoes produced a set of inhibitors with improved strength and selectivity.

Inflammatory lung diseases such as asthma are often characterised by an increase in HAT activity. Inhibitors based on anacardic acid are promising candidates for the treatment of inflammatory disease.