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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.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
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Translocation of Proteins into the Mitochondria01:19

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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The Proteasome02:18

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst 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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Regulation of Nuclear Protein Sorting01:45

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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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Protein Import into the Peroxisomes01:27

Protein Import into the Peroxisomes

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Cells contain membrane-bound organelles called peroxisomes that oxidize organic molecules by transferring hydrogen atoms to oxygen, producing hydrogen peroxide. Peroxisomes enzymatically convert the released hydrogen peroxide into water and oxygen.
Peroxisomal Protein Import:
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Anaphase Promoting Complex00:50

Anaphase Promoting Complex

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The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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Hypoxia-sensitive macrocycle inclusion complexes for targeted protein degradation.

Jiachan Lin1, Wenyan Wang1, An-Kang Ying2

  • 1School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.

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Summary

Hypoxia-responsive NaC4A-PROTACs enhance cancer therapy by improving PROTAC bioavailability and tumor delivery. This novel host-guest system enables targeted protein degradation, boosting anti-tumor efficacy.

Keywords:
AzocalixareneBRD4 degradationHost-guest chemistryHypoxiaPROTACs

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Area of Science:

  • Biochemistry
  • Materials Science
  • Oncology

Background:

  • PROteolysis TArgeting Chimeras (PROTACs) offer targeted protein degradation for cancer therapy.
  • Clinical PROTAC application is hindered by poor bioavailability, tumor distribution, and off-target effects.

Purpose of the Study:

  • To develop a hypoxia-responsive host-guest delivery system for PROTACs.
  • To enhance PROTAC bioavailability, tumor targeting, and anti-cancer efficacy.

Main Methods:

  • Design of NaC4A-PROTACs using azo-modified calixarene (Naph-SAC4A) as host and PROTACs as guest.
  • Formation of stable supramolecular complexes under normoxic conditions.
  • Hypoxia-induced azo bond cleavage and PROTAC release in tumor microenvironment.

Main Results:

  • NaC4A-PROTACs demonstrated stability in normoxia and efficient PROTAC release in hypoxia.
  • Enhanced PROTAC bioavailability and improved tumor-specific delivery observed in vitro and in vivo.
  • Significant anti-tumor effects demonstrated, targeting bromodomain-containing protein 4 (BRD4).

Conclusions:

  • NaC4A-PROTACs represent a novel supramolecular platform for hypoxia-targeted cancer therapy.
  • The system effectively overcomes PROTAC delivery limitations, enhancing precision and efficacy.
  • This approach offers a promising strategy for advanced PROTAC-based cancer treatments.