Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factors

Información del proyecto

SynTra

Identificador del acuerdo de subvención: 101039354

DOI

10.3030/101039354

Fecha de la firma de la CE 28 Abril 2022

Fecha de inicio 1 Junio 2022

Fecha de finalización 31 Mayo 2027

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 1 851 328,00

Aportación de la UE

€ 1 851 328,00

Coordinado por

UNIVERSITEIT LEIDEN
Netherlands

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

Período documentado: 2022-06-01 hasta 2024-11-30

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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.