VH032-PEG4-N3

Background Introduction

VH032-PEG4-N3 is a synthetic E3 ligase ligand-linker conjugate specifically designed for targeted protein degradation applications, leveraging the PROTAC (Proteolysis Targeting Chimera) technology. It features VH032, a potent ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase, conjugated to a polyethylene glycol (PEG4) spacer and an azide (N3) functional group for click chemistry compatibility. This modular design streamlines the development of next-generation PROTAC molecules for therapeutic and research purposes.

Mechanism

VH032-PEG4-N3 functions by selectively recruiting the VHL E3 ubiquitin ligase to target proteins of interest. When incorporated into a bifunctional PROTAC structure, the VH032 moiety binds to VHL, while the other end of the PROTAC is engineered to target a specific protein. The PEG4 spacer provides optimal flexibility and solubility, and the terminal N3 group enables modular conjugation via click chemistry, facilitating rapid assembly of diverse PROTACs. Upon successful recruitment, the E3 ligase promotes ubiquitination and subsequent proteasomal degradation of the target protein, resulting in selective protein knockdown within cells.

Applications

VH032-PEG4-N3 is valuable in the design and synthesis of custom PROTACs for targeted protein degradation studies. Researchers utilize this conjugate to quickly attach various target protein binders via click chemistry, expediting the creation of PROTAC libraries for drug discovery and mechanism-of-action studies. Its modular nature aids in optimizing PROTAC pharmacokinetics and cell permeability. Common application areas include oncology, neurodegenerative disease research, target validation, and the development of novel therapeutics that harness the cellular degradation machinery for hard-to-drug proteins.