New selective inhibitors of cap dependent proteins: synthesis, delivery and characterization

Project Leader: Prof. Jacek Jemielity Project period: 2017 - 2020
Project funding: TEAM, FNP
Project description:

The project aims at the design, synthesis, and evaluation of novel mRNA 5’ cap analogs as selective inhibitors of three major cap-related proteins: the eukaryotic translation initiation factor 4E (eIF4E) and the two decapping enzymes (DcpS and Dcp2). The proteins were selected due to their key roles in mRNA function and an already-confirmed status as molecular targets for cancer and neuromuscular diseases. To achieve the goal, we propose a comprehensive approach encompassing 1) generation of novel cap derivatives, either by traditional chemical synthesis or by combinatorial approach based on in situ click chemistry, 2) ideas for novel molecular probes and screening approaches specifically tailored for each of the proteins, 3) in-depth evaluation of the found inhibitors using biophysical, biochemical, and structural methods to understand their mechanism of action at the molecular level, 4) application of several cell-delivery strategies to demonstrate the biological potential in vivo.

Laboratory of Bioorganic Chemistry