"My vision is to eventually arrive at a fully integrated system that allows for efficient delivery of highly potent and specific bioactive peptides for the treatment of brain cancer."
- Dr. Bradley Pentelute
- Assistant Professor, Chemistry, Massachusetts Institute of Technology
About DSA-Funded 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.
"Brad is a fantastic colleague who has an unbridled passion for science and has amazing creativity. In the short time he has been in our department he has had a very positive impact. He always has a smile on his face, is always interested in science of his colleagues and he has huge amounts of energy that he channels to help all of us. He has made fantastic scientific progress this far and has fully taken advantage of the collaborative environment at MIT and the surrounding Medical Centers. You will be proud that you have selected Brad to be part of your family."
JoAnne Stubbe, Ph.D.
Massachusetts Institute of Technology
"Brad is perhaps the only person worldwide who has both the knowledge and technical skills to undertake this research, which requires spanning synthetic chemistry and toxin biochemistry/biology."
R. John Collier, Ph.D.
Harvard Medical School
- Chiocca, Ennio., M.D., Ph.D.
- John Sampson, M.D., Ph.D.
- Peter Fecci, M.D., Ph.D.
- Lautrette, G., Touti, F., Lee, H.G., Dai, P. Pentelute, B.L. (2016) Nitrogen arylation for macrocyclization of unprotected peptides. JACS, 138(27):8340-3
- Zhang, C., Welborn, M., Zhu, T., Santos, M., Yang, N., Van Voorhis, T., Pentelute, B.L. (2016) p-Clamp mediated cysteine conjugation. Nature Chemistry, (8)2, 120-128
- Vinogradova, E.V.*, Zhang, C.*, Spokoyny, A. M., Pentelute, B.L.*, Buchwald, S.L.* (2015) Organometallic palladium reagents for cysteine bioconjugation. Nature, 526(7575), 687-691 (*Co-corresponding authors and first authors)
- Cohen, D.T.,* Zhang, C.,* Pentelute, B.L.*, Buchwald, S.L.*, (2015) An Umpolung Approach for the Chemoselective Arylation of Selenocysteine in Unprotected Peptides, Journal of the American Chemical Society, 137(31), 9784-7 (*Co-corresponding authors and first authors)
- Zhang, C., Dai, P, Spokoyny, A., Pentelute, B.L., (2014) Enzyme catalyzed macrocyclization of long unprotected peptides. Organic Letters, 16(14): 3652-5
- Zou, Y., Spokoyny, A.M., Zhang, C., Simon, M.D., Yu, H., Lin, Y., Pentelute, B.L., (2014). Convergent Diversity-Oriented Side-Chain Macrocyclization Scan for Unprotected Polypeptides. Organic and Biomolecular Chemistry, 12(4): 566-73.