Development of 5′ cap-dependent activation of translation by click-to-release chemistry and hypoxia

• Applicant: Professorin Dr. Andrea Rentmeister
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551836943

Eukaryotic mRNA has recently become an important medical modality. However, the ability to control in which cells or tissues ectopic mRNA becomes activated is underdeveloped. We have previously established photocaged 5′ cap analogues to activate translation of ectopic mRNA by light. In this proposal, we aim to take the approach of cap-dependent activation to the next level and trigger translation by addition of a small molecule or hypoxia, a well-documented disease-relevant condition for tumors and other diseases. We will synthesize 5′cap analogs modified with a nitroaromatic/azobenzene group (RED-cap), strained alkene (TCO-cap), or boronic ester/acid (BOR-cap). The modifications are designed to block binding to the eukaryotic translation initiation factor 4E (eIF4E) and enable release of the native 5′cap structure by reductases, click-to-release chemistry or H2O2, respectively. We will test incorporation of the 5′caps into reporter mRNAs and assess how the absence and presence of these stimuli will affect translation. Finally, mammalian cell lines will be transfected with these mRNAs and activation of translation in response to hypoxia or click reagents will be investigated via suitable reporter and cell-death causing proteins.

• DFG Programme: Research Grants