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.