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ERC-grant for Sebastian Pomplun to cure disease by controlling gene expression with synthetic transcription factors

Sebastian Pomplun receives an ERC starting grant of 1.85 million Euros in five years. He wants to develop synthetic transcription factors that can enter cells and activate or deactivate specific genes. For example to disrupt cancer-related processes or to trigger the production of an important missing protein in sickle cell disease.

Pomplun's goal with his project SynTra is engineering synthetic transcription factors (STFs) that can enter cells and activate or deactivate specific genes. Traditional drugs target only a small fraction of the human proteome, while compounds that can be programmed to target specific genes could address many relevant disease mechanisms, right at their basis.

Engineering synthetic transcription factors and target unique genes

First, the drug discovery chemist will engineer transcription factors that can enter cells and bind to any given DNA base pair triplet. It will be like a new alphabet to read- the genetic code of life. Pomplun: 'After that I will prepare combinations of STFs that can target unique genes within the entire human genome with high specificity. With a hexameric transcription factor that recognizes eighteen DNA base pairs, I will target a specific gene promoter and trigger γ-globin production as a promising strategy for sickle cell disease treatment.'

Disrupt cancer-related DNA-processes

In the last part of his project, Pomplun will use STFs to displace the oncogenic transcription factor MYC from its DNA binding site. 'MYC is overexpressed in over 50% of all human cancers. If we displace it from it DNA binding site we can disrupt the oncogenic activity of this protein. A functional MYC inhibitor has game changing potential.’

This is not the first attempt, lessons have been learned

'It is a little early to say if and when these substances become therapeutics', Pomplun says. 'There have been several efforts over the last few decades to create modalities that can control genes and a lot lessons have been learned. In our design we try to address several of the issues related to previous attempts. For example by providing scaffolds with a better cell penetration.'

If everything works out well, SynTra will deliver powerful and practical synthetic tools for studying and targeting disease mechanisms. Researchers at the interface of biology and chemistry will then use the STFs developed in SynTra, for basic research and drug development. Pomplun: 'I hope that we can at least create a platform that makes talking about the development of therapeutics realistic.'

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