New peptide system for the targeted transport of molecules

In recent years, biomedicine and pharmacology have developed a large number of active substances capable of triggering, enhancing or inhibiting processes in mammalian cells. However, transporting these substances to exactly where they are needed remains a challenge in many cases.

The situation is similar when it comes to color marking certain structures inside cells for research or diagnostic purposes. It is true that mammalian cells have the ability to incorporate foreign substances by endocytosis. But this in no way guarantees transport to the desired site of action.

A new research approach that the biochemist from Bayreuth, Prof. Dr. Birte Höcker pursues with his research group is the rational design of peptides. These must be able to penetrate the interior of the cell from the outside and take with them active substances or attached dye molecules. Appropriate peptides for this purpose are rather small as they usually consist of less than 30 amino acids.

Until now, however, the problem was that these peptides – precisely because of their simplicity and small size – did not offer many possible applications. Indeed, there are only a few areas in the various structures inside the cell where they can anchor and deliver the molecules they carry. This drawback was overcome by the peptide developed in Bayreuth and Bristol. It is a basic peptide with a high content of arginine amino acids, and it has two essential components for its functionality. One allows the peptide to enter inside the cell and the other is able to interact with an acidic partner peptide.

This partner peptide is such that it can be placed in very different places inside the cell using established biochemical methods. Once proteins, larger molecular complexes, or organelles have been tagged with the partner peptide, they can be targeted by the base peptide that has entered the cell. Like a key in a lock, the basic peptide locks onto the acid peptide. Targeted placement of the acidic partner peptide is achieved by coupling it with molecules which are in turn introduced into the cell’s DNA by transfection.

The Anglo-German research team designed the two hitherto unknown de novo peptides using computer-aided protein design methods. The basis of this work was peptides with a coiled structure, which were described in a structure database. The computer-designed peptides were then synthesized in the lab. Here, biophysical methods and X-ray crystallography were used to identify the actual properties and behavior of the peptides. experiences with E.coli bacteria and eukaryotic cells revealed that the new peptide system is even suitable for transporting other peptides and proteins.

“Our research illustrates how the computational design of peptides and proteins, their subsequent synthesis and characterization in the laboratory, and live cell testing can intertwine when innovative solutions for biochemical or biomedical questions are sought,” says Professor Dr. Birte. Höcker, head of the Protein Design Group at the University of Bayreuth and corresponding author of the new study. “The new peptide system clearly shows that de novo design is a promising research approach in the search for methods to introduce drug or dye molecules into mammalian cells in a targeted and gentle way,” adds Dr. Guto Rhys, postdoctoral fellow at the Protein Design research group and l one of the first three authors.

Reference: Rhys GG, Cross JA, Dawson WM, et al. De novo engineered peptides for cellular delivery and subcellular localization. Nat Chem Bio. 2022. doi: 10.1038/s41589-022-01076-6.

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