Targeted degradation of proteins by small molecules: A novel tool for functional proteomics

D. Zhang, S. H. Baek, A. Ho, H. Lee, Y. S. Jeong, K. Kim

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

A novel strategy that targets protein for degradation has recently been developed by exploiting a p rotein-targeting chimeric molecule ('Protac'). Typically, the chimeric Protac is composed of a small-molecule ligand ('bait') on one end and a synthetic octapeptide on the other. This octapeptide is recognized by E3 ubiquitin ligase pVHL (von Hippel Lindau tumor suppressor protein), thereby recruiting a small molecule-bound protein ('prey') to pVHL for ubiquitination and degradation. Since selective degradation of a cellular protein generates a "loss of function" mutation, this protein knock-out strategy may be useful to study the function of a given protein or to evaluate whether a cellular protein is a potential target for drug intervention, in a manner reminiscent of gene knock-out or siRNA approaches. Herein, we show that a synthetic pentapeptide is sufficient to interact with pVHL E3 ligase, and that the pentapeptide-based Protac efficiently induces ubiquitination and degradation of target protein. Our results also demonstrate that the pentapeptide-based Protac can enter cells efficiently to exerts its biological activity effectively. These results suggest that the synthetic pentapeptide can be used either directly in the preparation of cell-permeable Protacs or as a template to develop peptidomimetic or non-peptide Protacs.

Original languageEnglish
Pages (from-to)689-697
Number of pages9
JournalCombinatorial Chemistry and High Throughput Screening
Volume7
Issue number7
DOIs
StatePublished - Nov 2004

Keywords

  • E3 ubiquitin ligase
  • Estradiol (E2)
  • Estrogen receptor (ER)
  • Hypoxia-inducing factor-1α (HIF-1α)
  • Post-genomic era
  • Proteasome
  • Protein-targeting chimeric molecule (Protac)
  • Ubiquitin
  • Von Hippel Lindau tumor suppressor protein (pVHL)

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Organic Chemistry

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