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Targeted protein degradation at the host-pathogen interface.

Christoph Grohmann1,2, Danushka S Marapana1,2, Gregor Ebert3

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Molecular Microbiology
|November 24, 2021
PubMed
Summary

Targeted protein degradation (TPD) offers a novel approach to combat infectious diseases by eliminating drug-resistant pathogens. Proteolysis-targeting chimeras (PROTACs) degrade target proteins, including previously "undruggable" ones, showing promise for new treatments.

Keywords:
Proteolysis-targeting chimerasbacteriadrugintracellular infectionparasitespathogenic proteinsresistanceviruses

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Infectious Diseases

Background:

  • Infectious diseases pose a significant global health challenge.
  • Emerging drug and vaccine resistance necessitate innovative therapeutic strategies.
  • Traditional small-molecule drugs often fail to target essential non-enzymatic proteins, labeled as "undruggable".

Purpose of the Study:

  • To review advances in Targeted Protein Degradation (TPD) for infectious disease treatment.
  • To explore the potential of TPD, specifically Proteolysis-Targeting Chimeras (PROTACs), against drug-resistant pathogens.
  • To discuss the application of TPD at the host-pathogen interface.

Main Methods:

  • Review of current literature on Targeted Protein Degradation (TPD) and Proteolysis-Targeting Chimeras (PROTACs).
  • Analysis of TPD's mechanism utilizing the ubiquitin-proteasome system for selective protein elimination.
  • Discussion of PROTACs' efficacy in degrading target proteins, including those previously considered undruggable.

Main Results:

  • PROTACs have demonstrated success in degrading various cancer-associated proteins, with candidates in clinical development.
  • TPD offers a powerful strategy to overcome resistance to existing treatments for infectious diseases.
  • PROTAC-mediated TPD shows significant potential for targeting pathogenic proteins.

Conclusions:

  • Targeted Protein Degradation (TPD) represents a promising therapeutic avenue for infectious diseases, particularly those with drug resistance.
  • PROTACs offer a mechanism to degrade challenging, previously undruggable pathogenic proteins.
  • Further development of TPD strategies holds potential for combating viral, bacterial, and parasitic infections.