Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factors

Informations projet

SynTra

N° de convention de subvention: 101039354

DOI

10.3030/101039354

Date de signature de la CE 28 Avril 2022

Date de début 1 Juin 2022

Date de fin 31 Mai 2027

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 851 328,00

Contribution de l’UE

€ 1 851 328,00

Coordonné par

UNIVERSITEIT LEIDEN
Netherlands

Periodic Reporting for period 1 - SynTra (Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factors)

Période du rapport: 2022-06-01 au 2024-11-30

Résumé du contexte et des objectifs généraux du projet

The ERC StG project SynTra aims to develop synthetic miniproteins able to enter cells, bind to specific DNA sequences and modulate disease related gene transcription. The Pomplun Lab proposes to utilize a combination of rational design, combinatorial chemistry and synthetic protein modification technology to achieve this goal.
Targeting specific DNA sequences is challenging when utilizing small molecules. On the other hand, macromolecules (or macromolecular complexes), such as transcription factor proteins that are able to recognizes specific DNA sequences, are not able to enter cells. We propose the development of chemically engineered transcription factor analogs able to enter cells and the cell nucleus and bind to DNA. By targeting specific disease related sequences, such as the enhance box of the oncogenic transcription factor MYC, we aim to tackle gene related disease development.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

To date we tested the suitability of different natural transcription factor scaffolds for function retaining chemical modifications. We identified basic helix loop helix transcription factors as suitable structures, and identified a number of chemical modifications that a) maintain the proteins DNA binding activity and b) enable these synthetic proteins to enter cells. In a number of functional in vitro and in cell assays we show how our miniproteins can modulate disease related gene transcription. In particular, we identified variants that can inhibit the oncogenic transcription factor MYC with a high potency.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The lead compound developed within this ERC StG project is a highly promising candidate for the development of advanced therapeutics to treat MYC driven cancers. We plan to proceed to test this compound in more advanced systems such as MYC dependet tumor organoids and mouse models, in the near future.