By Chintan Soni
Proteins are powerful and versatile molecules with immense potential in medicine and the materials industry, but they are built from just 20 natural α-amino acids, linked through an α- amide backbone, limiting the range diversity of structures and functions they can achieve. In this work, C-GEM researchers used their directed evolution platform, START, to engineer aminoacyl-tRNA synthetase (aaRS) enzymes that allow cells to incorporate entirely new, non-α-amino acid building blocks. For the first time, this enabled the synthesis of proteins with modified backbones in mammalian cells. These redesigned proteins remain stable under normal conditions but can be selectively broken down when triggered, opening new possibilities for controlled cargo release and smart therapeutics. The engineered enzymes also provide a foundation for further redesigning the cell’s protein-making machinery to build even more diverse, next-generation biomolecules.
This work involved contributions from the Chatterjee lab and Schepartz lab.