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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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Peptide-Based PROTACs: Transitioning from Static Paradigm to a Dynamic Landscape within Targeted Protein Degradation.

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Peptide-based PROTACs (pPROTACs) offer a versatile approach to protein degradation, overcoming limitations of traditional small-molecule PROTACs. Emerging strategies expand their therapeutic potential for undruggable targets.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality for targeted protein degradation.
  • Small-molecule PROTACs face limitations including narrow target scope and dependence on specific binding pockets.
  • Peptide-based PROTACs (pPROTACs) present a complementary strategy with enhanced specificity and adaptability.

Purpose of the Study:

  • To review recent advancements in peptide-based PROTAC (pPROTAC) design and conjugation.
  • To highlight novel nonclassic and deconstructive pPROTAC architectures.
  • To discuss bioPROTACs as genetically encodable protein degraders.

Main Methods:

  • Review of current literature on pPROTAC design and conjugation strategies.
  • Analysis of emerging supramolecular and genetic assembly approaches for pPROTACs.
  • Discussion of bioPROTAC technology and its implications.

Main Results:

  • Classical pPROTACs demonstrate improved target scope and modularity.
  • Nonclassic and deconstructive pPROTAC architectures offer innovative degradation mechanisms.
  • BioPROTACs represent a genetically encoded platform for protein degradation.

Conclusions:

  • pPROTACs are an evolving class of targeted protein degradation agents.
  • pPROTAC strategies complement small-molecule PROTACs, expanding therapeutic possibilities.
  • Advanced pPROTAC designs broaden the range of degradable targets, including previously undruggable proteins.