Conformational Dynamics in the Cell Membrane Interactions of Bispecific Targeted Degrader Therapeutics

Proteolysis targeting chimeras (PROTACs) offer vast new
therapeutic
opportunities, but their physicochemical properties are difficult
to combine with optimal cell permeability and exposure at the target
sites. We have systematically analyzed a data set of more than 3500
PROTACs to investigate how the choice of ubiquitin E3 ligands, linker
design, and global molecular properties can be optimized to achieve
the desired cell membrane interactions and ultimately membrane permeability
and intracellular exposure. We find that conformational flexibility
leads to environment-dependent shielding of polar functions and improved
interactions with cell membranes but that at the same time, extended,
linear conformations within the membrane are beneficial. Linker composition
was a major factor in determining the folding propensity. Collectively,
our results suggest that strategies to rationally design linkers and
to shield polarity selectively within the protein-of-interest (POI)
ligand and/or E3 ligand domains rather than more extensive folding
may be beneficial in the design of permeable and effective PROTACs.