Activable Targeted Protein Degradation Platform Based on Light-triggered Singlet Oxygen

Abstract

Targeted protein degradation technologies (e.g., PROTACs) that can selectively degrade intracellular protein are an emerging class of promising therapeutic modalities. Herein, we describe the conjugation of photosensitizers and protein ligands (PS-Degrons), as an activable targeted protein degradation platform. PS-Degrons are capable of degrading protein of interest via light-triggered 1O2, which is orthogonal and complementary to existing technologies. This generalizable platform allows controllable knockdown of the target protein with high spatiotemporal precision. Our lead compound PSDalpha induces a complete degradation of human estrogen receptor α (ERα) under visible light. The high degrading ERα efficacy of PSDalpha enables an excellent anti-proliferation performance on MCF-7 cells. Our results establish a modular strategy for the controllable degradation of target proteins, which can hopefully overcome the systemic toxicity in clinical treatment of PROTACs. We anticipate that PS-Degrons would open a new chapter for biochemical research and for the therapeutics.

Photoexcited graphene oxides activate silent viruses in bacteria with dependency on their sizes

“…To further investigate whether oxidative stress was actually responsible for the prophage activation by GO-1 and GO-2, a series of well-known antioxidants ( N -acetyl- l -cysteine: NAC, l -glutathione: GSH, dl -dithiothreitol: DTT and l -ascorbic acid: VC) were applied. 28 With the addition of the antioxidants, the ROS content in E. coli (λ+) treated with photo-excited GO-1 and GO-2 was reduced to the normal level. Notably, the prophage induction of GO-1 and GO-2 was almost suppressed by the antioxidants (Fig.…”

Targeted Recruitment and Degradation of Estrogen Receptor α by Photothermal Polydopamine Nanoparticles for Breast Tumor Ablation

“…The specific binding of PDA‐EST and PDA‐RAL to ER α were first verified by the competitive binding experiments using coumestrol as a fluorescent tracer [ 23 ], [ 24 ] ( Figure A). Compared to nontargeted PDA, PDA‐EST and PDA‐RAL NPs could efficiently displace coumestrol from the ligand binding pocket, indicating high binding affinities to ER α .…”

PDTAC: Targeted Photodegradation of GPX4 Triggers Ferroptosis and Potent Antitumor Immunity

“…To utilize this localized reactivity, a targeting ligand that binds to the POI can then direct most of the photoinduced 1 O 2 to act on the target protein. With the high reactivity of 1 O 2 to oxidize amino acids or to break the backbones, the POI could be inactivated or even degraded. , In principle, the three modules of PDTAC can be assembled to generate versatile molecules to degrade desired proteins. The coupling of protein degradation to light activation endows PDTAC with high spatiotemporal control, which would be highly beneficial for drug development.…”