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Related Concept Videos

Regulated Protein Degradation02:58

Regulated Protein Degradation

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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The Proteasome01:13

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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The Proteasome Structure01:17

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Stimuli-Responsive PROTACs for Controlled Protein Degradation.

Keli An1, Xuqian Deng2, Hongli Chi2

  • 1The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, 710049, China.

Angewandte Chemie (International Ed. in English)
|July 20, 2023
PubMed
Summary

Stimuli-responsive Proteolysis Targeting Chimeras (sr-PROTACs) were developed using a caging strategy to control protein degradation. These sr-PROTACs activate in response to pathological cues or external triggers, enabling targeted therapy with reduced toxicity.

Keywords:
Drug DeliveryPROTACsPersonalized MedicineProdrugsProtein Degradation

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic approach for challenging drug targets.
  • Clinical application of PROTACs is limited by potential on-target toxicity.
  • Developing controlled activation mechanisms for PROTACs is crucial for safe and effective therapy.

Purpose of the Study:

  • To design and synthesize stimuli-responsive PROTACs (sr-PROTACs) with controllable activation.
  • To leverage pathological cues and external triggers for site-specific PROTAC activation.
  • To evaluate the efficacy and safety of sr-PROTACs in vitro and in vivo.

Main Methods:

  • Developed a generalized caging strategy for synthesizing sr-PROTACs with cleavable linkers.
  • Utilized various pathological cues (ROS, phosphatase, H2S, hypoxia) and external triggers (UV light, X-ray, bioorthogonal reagents) for activation.
  • Tested sr-PROTACs for selective uptake and controlled protein degradation in vitro.
  • Administered sr-PROTACs in vivo to assess plasma exposure, tumor targeting, and therapeutic effect.

Main Results:

  • Synthesized diverse sr-PROTACs with "turn on" features for protein degradation.
  • Achieved site-specific activation and traceless release of PROTACs via de-caging and self-immolative cleavage.
  • Demonstrated selective uptake and controlled protein degradation in vitro.
  • Showcased potent tumor remission in vivo with sr-PROTACs activated by tumor-specific phosphatase or low-dose X-ray irradiation.

Conclusions:

  • The developed caging strategy provides a versatile platform for creating activatable PROTACs.
  • sr-PROTACs enable precise control over protein degradation, mitigating toxicity concerns.
  • This approach holds potential for personalized medicine, including targeted therapies and advanced biomaterials.