Diarylethene-based photoswitchable peptides for inhibiting autophagy in a spatio-temporally resolved manner

• Applicant: Dr. Serhii Koniev
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528656466

Autophagy provides fuel for generating energy and building blocks for renewing cellular components, thereby enhancing the overall fitness of a cell in its response to starvation and other types of stress. Dysregulation of autophagy is associated with a wide range of diseases, including neurodegenerative disorders and cancer. In this project, I propose the development of a specific autophagy inhibitor whose activity will be possible to regulate by the action of light. The inhibitor is based on the helical peptide ATG16L1, derived from the protein-protein interaction (PPI) interface of the ATG16L1/ATG12-ATG5 complex. This PPI plays a crucial role in the elongation stage of autophagy. The ATG16L1 helix will be "stapled" with a diarylethene photoswitch (DAE), allowing switching the inhibition ON/OFF by irradiation with light of selected wavelengths. The DAE-enabled photoregulation of the inhibitor will allow for spatial and temporal control of its activity, potentially minimizing off-target effects in the in vivo settings. The project is grounded on the known methods of DAE-coupling to helical peptides and will focus on determining the appropriate molecular framework for controlling autophagy and proof-of-principle demonstration. The resulting light-switchable inhibitor has the potential to be used in photopharmacological applications, particularly in cancer therapy, where inhibition of autophagy is beneficial.

• DFG Programme: WBP Position