Targeted Protein Degradation by Photosensitization Triggering Ferroptosis for Enhanced Antitumor Immunity

Description

Proteolysis-targeting chimera (PROTAC) has emerged as a promising technology for targeted protein degradation. By using a tailor-made protein degrader consisting of a ligand that can bind to a protein of interest and another ligand that can bind to an E3 ubiquitin ligase connected covalently with an appropriate linker, it can degrade diseasecausing proteins by hijacking the ubiquitin–proteasome system. This approach has found potential application in cancer treatment. Despite the various advantages, this strategy still has some limitations that hinder its clinical translation. The PROTACs developed so far generally show low systemic bioavailability and limited cell permeability. The off-target biodistribution due to the non-selective expression of E3 ligases in the target and normal cells, as well as the Hook effect that favors the formation of binary over ternary complexes may also lead to severe side effects and reduced potency,respectively. Moreover, the options of E3 ligases remain very limited. An alternative approach has recently been proposed which utilizes a photosensitizer conjugated with a protein-binding ligand to generate reactive oxygen species (ROS) upon light irradiation for degradation of the bound protein. The molecular design of these protein degraders is simpler and more flexible. As E3 ligases are no longer the weapon for protein degradation, this approach can resolve the relevant drawbacks and relax the requirements of the linkers, and just the protein targeting would be a critical issue. Moreover, owing to the short diffusion range of the short-lived ROS, the degradation of proteins can occur with high spatiotemporal precision. However, development of this approach is still in the infancy, and only a handful of examples have been reported so far. As a result, we propose herein a project to develop novel photosensitizers for targeted photodegradation of two important proteins, namely the cysteine/glutamate antiporter system Xc- and the lipid repair enzyme glutathione peroxidase 4 with a view to triggering immunogenic cell death through ferroptosis, which is a unique form ofregulated cell death. The proposed studies involve the design and synthesis of a series of zinc(II) phthalocyanine-based photosensitizers substituted with an inhibitor of these proteins and a tumor-targeting peptide to promote the cellular uptake into the target cells. It is believed that these conjugates can induce photodegradation of these proteins specifically, triggering ferroptotic cell death and potent antitumor immunity. This hypothesis will be validated through a series of carefully designed experiments with a range of cell lines and tumor-bearing mice.