Impact of Linker Composition on VHL PROTAC Cell Permeability

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Developing cell-permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) presents significant challenges due to their complex structures.
• PROTACs often fall outside the conventional limits of orally druggable chemical space.

Purpose of the Study:

• To investigate the impact of linker design on the cell permeability of VHL PROTACs.
• To identify structural features that correlate with enhanced passive cell permeability in VHL PROTACs.

Main Methods:

• Design and synthesis of nine novel VHL PROTACs with varying linker compositions.
• Determination of PROTAC solution conformations in nonpolar solvents using biophysical techniques.
• Correlation analysis between PROTAC conformation, polar surface area, and cell permeability.

Main Results:

• The linker component significantly influences the passive cell permeability of VHL PROTACs.
• High cell permeability is associated with PROTACs adopting folded conformations with low solvent-accessible 3D polar surface area in nonpolar environments.
• Intramolecular hydrogen bonds, NH-π, and π-π interactions stabilize low-polarity conformations, enhancing cell permeability.

Conclusions:

• PROTAC design for cell permeability should focus on linkers that enable shielding of polar surface areas, particularly within the VHL ligand, in nonpolar environments.
• Understanding conformational preferences and non-covalent interactions is crucial for optimizing PROTAC delivery and oral bioavailability.