Peptide Macrocyclization Enabled by Cysteine Arylation
Bradley Pentelute
Pfizer-Laubach Career Development Asst Professor, MIT
Here we report a novel and robust method for macrocyclization of unprotected peptides using cysteine arylation. Importantly, this chemistry allowed for peptide modifications that imparted favorable cell penetration and proteolytic stability. This approach expands the biomolecular toolkit for the facile modification cysteine contained within peptides.
About Dr. Pentelute's Research:
Biomolecules such as peptides and proteins have become powerful agents in biotechnology for the treatment of cancer. Despite this success, many of these agents are limited to extracellular uses due to their incapability to cross the cell plasma membrane. Because of this, the cytosol is considered "undruggable" with biomolecules. Here we propose to use a very recent discovery in our lab based on fluorine containing peptides that kill brain tumor cells by striking an intracellular protein target. Our first aim is to develop a robust and versatile fluorine stapling chemistry to transform the peptides into highly selective, potent, and cell penetrating species. Our second aim is decipher how this transformation affects the bioactivity and cell permeability of these peptides so we can use them to disrupt a critical set of interactions inside the cell that will ultimately lead to death of brain tumor cells. Upon completion of this research proposal, brain cancer researchers will be enabled with a powerful toolbox of therapeutic agents thereby fundamentally changing the way cancer is studied and treated.