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

自噬提供了产生能量的燃料和更新细胞成分的构件，从而增强了细胞在应对饥饿和其他类型压力时的整体适应性。自噬的失调与广泛的疾病相关，包括神经退行性疾病和癌症。在这个项目中，我建议开发一种特定的自噬抑制剂，其活性将可能通过光的作用来调节。该抑制剂基于螺旋肽ATG 16 L1，其衍生自ATG 16 L1/ATG 12-ATG 5复合物的蛋白质-蛋白质相互作用（PPI）界面。这种PPI在自噬的延伸阶段起着至关重要的作用。ATG 16 L1螺旋将用二芳基乙烯光电开关（DAE）“装订”，允许通过用选定波长的光照射来切换抑制ON/OFF。抑制剂的DAE激活的光调节将允许其活性的空间和时间控制，潜在地最小化体内环境中的脱靶效应。该项目基于已知的DAE偶联到螺旋肽的方法，并将重点确定用于控制自噬和原理验证的适当分子框架。所得到的光可切换抑制剂具有用于生物药理学应用的潜力，特别是在癌症治疗中，其中抑制自噬是有益的。

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.