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Prof. Brad L Pentelute
Professor of Chemistry
Extramural Member, Koch Institute for Integrative Cancer Research
Primary DLC
Department of Chemistry
MIT Room:
18-596
(617) 324-0180
blp@mit.edu
https://chemistry.mit.edu/profile/bradley-l-pentelute/
Assistant
Michael Lewy
(617) 253-1805
mlewy@mit.edu
View Feature
Areas of Interest and Expertise
Virulence Factors
Mirror Image Proteins
Protein Translocation
Rapid Total Protein Synthesis
Microbes
Peptide Synthesis
Research Summary
The Pentelute Lab invents new protein modification chemistries, adapts Nature's biological machines for efficient drug delivery into cells, and creates new technologies to rapidly manufacture peptides and proteins.
Nature has developed molecular machines to rapidly assemble, modify, and deliver proteins into cells. Inspired by these mechanisms, the Pentelute Lab explores new cysteine and lysine arylation chemistries for the efficient and selective modification of proteins, employs chemical biology to systematically dissect how anthrax toxin hijacks biomolecules into cells, and develops fast flow platforms for the rapid production of peptides and other chemically modified biomolecules. We aim to invent new chemistry to modify Nature’s proteins to enhance their therapeutic properties for human medicine. This new chemistry needs to be protein compatible, site-selective, quantitative, and carried out in water at reasonable temperatures to maintain protein integrity and function. The Pentelute Lab has met these challenges and has developed a series of highly efficient and selective methodologies that can modify cysteine and lysine side chains within peptides and proteins. These reactions can be catalyzed by enzymes or even promoted by a motif discovered by our group, coined a ‘pi-clamp’. This extensive protein modification toolkit has enabled the production of potent molecules, including peptide macrocycles that cross cell membranes and the blood-brain barrier to disrupt cancer or antibody-drug conjugates to kill breast cancer cells.
We are also focused on the delivery of large biomolecules into the cell cytosol and nucleus. The group has developed a chemical approach for the systematic investigation of a nontoxic form of anthrax toxin, which transports enzymes into cells via a protective antigen-protein pump. This pump can deliver a wide range of cargo molecules including antibody mimics, mirror-image proteins, small molecules, and enzymes. Once in the cytosol, the cargo activates biologically and in certain cases perturbs protein-protein interactions that drive cancer. Noteworthy, we discovered that by simply installing a single D-amino acid on a large L-protein turns off a key mechanism for cytosolic protein degradation. This discovery will aid in the development of durable cell-based protein therapeutics. In parallel, we are actively investigating delivery of therapeutic antisense oligonucleotides to the cell nucleus with cell-penetrating peptides, a large collection of chemical vectors abundant in Nature.
We have invented a fully automated fast-flow machine to accelerate the chemical manufacture of polypeptides. The Pentelute Lab has built the world’s fastest and most efficient peptide synthesizer that can produce amide bonds orders of magnitude faster than commercially available instruments. The machine is inspired by Nature’s ribosome that can incorporate 9 amino acids into a polypeptide chain per second. While our technology is not as fast as the ribosome, it can form one amide bond in 10 seconds or less. This technology not only facilitates rapid polypeptide and even small protein generation, but it has enabled the group to carry out entire D-scans of proteins to investigate their folding and functions. This technology may solve the manufacturing problem for personalized peptide-based cancer vaccines, a challenge we are currently tackling.
Recent Work
Projects
July 1, 2020
Abdul Latif Jameel Clinic for Machine Learning in Health (J-Clinic)
Deep Learning Peptide Representations for Optimal Cellular Delivery of Gene-Editing Cargo
Principal Investigator
Brad Pentelute
January 18, 2017
Department of Chemistry
Using Chemistry to Probe Anthrax Toxin Protein Translocation
Principal Investigator
Brad Pentelute
May 27, 2015
Department of Chemistry
Cysteine Arylation
Principal Investigator
Brad Pentelute
September 17, 2013
Department of Chemistry
Pentelute Lab
Principal Investigator
Brad Pentelute
September 17, 2013
Department of Chemistry
New Chemical Methods for Peptide Macrocyclization
Principal Investigator
Brad Pentelute
September 17, 2013
Department of Chemistry
New Tools and Instrumentation for Biomolecule Synthesis
Principal Investigator
Brad Pentelute
August 11, 2011
Department of Chemistry
Protein Translocation Probed with Chemical Synthesis: Intracellular Translocation Delivery Platforms
Principal Investigator
Brad Pentelute
August 11, 2011
Department of Chemistry
Biological Properties of Mirror Image Proteins
Principal Investigator
Brad Pentelute
Video
10.12.23-AI-Driven-Pentelute
October 12, 2023
Conference Video
Duration: 31:11
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We're facing a challenge in the world of chemistry: our lack of data is slowing down how we can use clever computer programs, known as machine learning, to create powerful new medicines. In this piece, I'll walk you through what we're doing to solve this problem by creating data highways from millions of small molecules, peptides and small proteins. We are now able to use machine learning to discover and create new functional molecules quickly. Sometimes, these computer-designed molecules are even better than what we can make ourselves! Our next step is to create an infinite loop where we automatically design, build, and test potential new medicines.
10.12.23-AI-Driven-Panel
October 12, 2023
Conference Video
Duration: 22:39
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Panel Discussion
Future Science at the Molecular Level
August 10, 2023
MIT Faculty Feature
Duration: 18:30
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Bradley L. Pentelute
Professor of Chemistry
Pentelute-Japan-1.28.2021
January 28, 2021
Conference Video
Duration: 30:43
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Brad Pentelute
Associate Professor of Chemistry
MIT Department of Chemistry
Related Faculty
Prof. Frederick D Greene
Professor of Chemistry, Emeritus
Adam J Rieth
Graduate Student
Prof. Daniel Suess
Associate Professor of Chemistry