Self-Assembly of Proteolysis Targeting Chimeras Via Reversible Bioorthogonal Reactions

15 September 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Targeted protein degradation (TPD) by PROteolysis TArgeting Chimeras (PROTACs) is of great interest for probe molecule and drug development. However, current bivalent PROTACs are rule-breaking molecules with sub-optimal cellular permeability, solubility, and other drug-like properties. In this study, we report a novel approach for TPD by Self-Assembled Proteolysis TArgeting Chimeras (SAPTACs) in which the target protein and E3 Ubiquitin ligase ligands assemble in cellulo via reversible, bioorthogonal reactions. SAPTACs that me-diate the degradation of the Von Hippel Landau (VHL) E3 Ubiquitin ligase are described. We show that pseu-do-homodimeric degraders for VHL can be assembled in situ through the interaction of VHL ligands linked to phenylboronic acid and catechol as well as to o-acetlyphenylboronic acid and an alkoxyamine. The efficiency of VHL degradation by these SAPTACs is linked to the strength of the reversible covalent interaction.

Keywords

PROTAC
degrader
reversible covalent chemistry
VHL

Supplementary materials

Title
Description
Actions
Title
Supplementary Information
Description
Supplementary data and full experimental protocols.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.