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Protein engineering through total chemical synthesis

Publication in ACS Central Science shows how full synthesis of proteins can be used to manipulate their structure and function

2024/03/14 by

Drug development is a complex process that requires a series of steps. Starting with the research of a disease, through to the identification of an associated target protein and finally to the development of a small molecule (ligand) that can target the disease. Here, cavities in the protein structure, so-called binding pockets, play a critical role. The developed ligand interacts with the target protein to achieve the desired therapeutic effect. A major challenge is to achieve selective interactions with the target protein without affecting other related proteins.

Prof. Felix Hausch's research group is working intensively on the development of ligands that interact with the target protein FKBP51. This protein is associated with chronic pain, depression and obesity. For a long time, it has been difficult to find selective ligands that can distinguish between FKBP51 and its related protein FKBP52. This is crucial as both proteins have different biological functions despite having a similar structure. A significant discovery was that the binding pocket of FKBP51 can enlarge, in contrast to FKBP52, which allows differentiation. Although this change is dynamic, by chemically modifying the protein, the pocket can be kept permanently open to study the protein in more detail. A recently published paper in the renowned journal ACS Central Science from the research group of Prof. Hausch in collaboration with the research groups of Prof. Lermyte and Prof. Pentelute (MIT, USA) exactly addresses this topic. The work was funded by the Hessian Ministry of Science and Art, which supports the LOEWE focus TRABITA, a research network for the investigation of TRAnsient BIndungsTAschen.

“Through the complete chemical synthesis of the crucial domain of FKBP51, this protein could be modified to create a permanently open binding pocket,” explains Anna Charalampidou, the first author of the publication. “This led to an up to 39-fold improvement in binding affinity for conformationally selective ligands and opens up a unique system for the development of ligands for this rare conformation.” Overall, the results show how automated flow peptide synthesis can be used for precise protein engineering.