title: Targeted degradation of proteins by small molecules: a novel tool for functional proteomics.
abstract: A novel strategy that targets protein for degradation has recently been developed by exploiting a protein-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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 907 Rose Street, Lexington, Kentucky 40536, USA
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: S-H
authors.initials: SH
authors.lastname: Baek
authors.forename: A
authors.initials: A
authors.lastname: Ho
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: Y S
authors.initials: YS
authors.lastname: Jeong
authors.forename: K
authors.initials: K
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D006801:Humans; D007202:Indicators and Reagents; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D007202:Indicators and Reagents; D011506:Proteins; D025801:Ubiquitin