Pentelute, Bradley L. - Massachusetts Institute of Technology

研究领域

Throughout evolution, Nature has developed molecular machines to rapidly manufacture, tailor, and deliver large functional biopolymers such as proteins into specific cells. Inspired by these mechanisms of Nature, the Pentelute Lab has aimed to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins. A main goal of the Pentelute Lab is to invent new chemistry to modify Nature’s proteins to enhance their therapeutic properties for human medicine. This goal has posed immense challenges because proteins contain 20 amino acids that present different reactive functional groups and have a 3D shape that is moderately stable. In light of this, the newly developed 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 chemistries that can modify the amino acid cysteine and lysine within peptides and proteins. These newly developed chemistries can be catalyzed by enzymes or even promoted by a motif discovered by Pentelute’s group, which is coined a ‘pi-clamp’. This extensive protein modification toolkit has enabled the production of some powerful molecules including peptide macrocycles that cross cell membranes to disrupt cancer or antibody drug conjugates to kill breast cancer cells. The Pentelute group is also focused on the delivery of large biomolecules into the cell cytosol. 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. The Pentelute Lab has recently discovered that the protein pump can deliver a wide range of cargo molecules into cells 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. The Pentelute group made a noteworthy cell biology discovery with this biomolecular delivery platform: the act of simply installing a single D-amino acid on an otherwise 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.

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A novel, safe, fast and efficient treatment for Her2‐positive and negative bladder cancer utilizing an EGF‐anthrax toxin chimera 2020, Publications Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism 2020, Publications Automated Flow Synthesis of Tumor Neoantigen Peptides for Personalized Immunotherapy 2020, Publications Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide 2020, Publications Mutations in pmrB Confer Cross-Resistance between the LptD Inhibitor POL7080 and Colistin in Pseudomonas aeruginosa 2019, Publications Chimeras of Cell-Penetrating Peptides Demonstrate Synergistic Improvement in Antisense Efficacy 2019, Publications Studies on a landscape of perfluoroaromatic-reactive peptides 2019, Publications In-solution enrichment identifies peptide inhibitors of protein–protein interactions 2019, Publications Conformational Stabilization and Rapid Labeling of a 29-Residue Peptide by a Small Molecule Reaction Partner 2019, Publications Affinity-based capture and identification of protein effectors of the growth regulator ppGpp 2019, Publications Arylation Chemistry for Bioconjugation 2019, Publications A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins 2019, Publications Blood–brain-barrier organoids for investigating the permeability of CNS therapeutics 2018, Publications Analyzing Dynamic Protein Complexes Assembled On and Released From Biolayer Interferometry Biosensor Using Mass Spectrometry and Electron Microscopy 2018, Publications Antibody–Bactericidal Macrocyclic Peptide Conjugates To Target Gram‐Negative Bacteria 2018, Publications Structure of HIV TAR in complex with a Lab-Evolved RRM provides insight into duplex RNA recognition and synthesis of a constrained peptide that impairs transcription 2018, Publications Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability 2018, Publications Xenoprotein engineering via synthetic libraries 2018, Publications Amide-forming chemical ligation via O-acyl hydroxamic acids 2018, Publications Designing Well-Structured Cyclic Pentapeptides Based on Sequence–Structure Relationships 2018, Publications