Biomacromolecule-based therapies are of keen interest to the pharmaceutical industry because macromolecules engage in highly specific interactions in biological systems compared to traditional small molecules. Despite their success, macromolecular therapies have almost exclusively been limited to extracellular targets due to the significant challenge in delivering macromolecules to the cytoplasm. As a result, the therapeutic potential of biomacromolecules has yet to be fully realized for intracellular targets.

To address this challenge, David Liu’s laboratory is using phage-assisted continuous evolution (PACE) to reprogram botulinum neurotoxin (BoNT) proteases. BoNTs are macromolecules with an inherent cytosolic delivery mechanism, making it an ideal vehicle for cleaving intracellular targets. David Liu’s team has successfully demonstrated their approach by targeting VAMP7, an intracellular protein with aberrant activity associated with motor neuron diseases. This is an important breakthrough in using biomacromolecules for intracellular targets and could find utility in addressing a range of diseases.