Small molecules can have a considerable effect in the body, for example if they change the activity of enzymes or cell receptors. Most of today's medicinal products target easily accessible structures – they often imitate small endogenous molecules and, for example, bind to proteins that project from cells. However, the options for intervening in biological processes in this way appear to be running increasingly low. In contrast, less research has been conducted on the less accessible field of the countless interactions that proteins undergo among each other – protein molecules are incessantly attaching to each other to form complexes and then detach from each other again soon after. If scientists were to succeed in intervening specifically in these interactions, this would lead to giant steps in the development of truly innovative medicinal products.
A breakthrough in this field has now been achieved by the group led by Ronald Kühne at the FMP. For many years, this group has been working on identifying the main properties of protein-protein interactions in which proline-rich structural motifs are involved and, building on this knowledge, developing active substances. In the process, two major hurdles have to be overcome fundamentally. First, the bond between the protein molecules involved is comparatively weak – which makes sense biologically, since they are supposed to separate from each other again when the need arises. Second, the binding is highly specific, despite the fact that the structural motifs of different complexes have certain similarities. Ronald Kühne overcame both hurdles with the development of so-called proteomimetics (ProM for short), with which small molecules imitate the structural motifs of larger proteins and can even have a higher affinity than their natural role models. Proteins are long thread-like molecules made up of chains of amino acids, which are folded into complicated structures – it is the precise shape of this cluster that determines the function of a protein molecule. In contrast, a ProM is a small molecule that can be incorporated into a short chain of amino acids and forces them into a certain shape, without the large cluster being necessary for this.
The development of the ProMs started on the computer: Kühne and his colleagues can calculate in advance which shape a hypothetical molecule will have and how it will interact with a protein; the hypothetical molecules are presented as 3D images. "You need a bit of imagination, a good idea and at the same time the necessary experience as a chemist," is how Kühne describes the creative process. Kühne's aim was to imitate a widespread structural motif in proteins, in which the amino acid proline occurs particularly frequently. "The decisive thing was to design a small molecule that can precisely mimic this form but, in contrast to amino acid chains, is rigid rather than freely mobile," explains Ronald Kühne. In the meantime, he has a whole series of such molecules at this disposal, which can be combined like building blocks. The small rigid molecules mimic the outer structure of the amino acids perfectly, but they have a completely different chemical structure. It was just as much of a challenge to find synthesis pathways in order to turn the imaginary structures into reality – this was achieved in the group led by Hans-Günther Schmalz at the University of Cologne.
Ronald Kühne and his colleagues have now provided the first evidence of what can be achieved with the ProM building blocks. They used these building blocks to develop an active substance that inhibits cell migration and thus prevented the spread of aggressive breast cancer cells in culture vessels. The active substance binds to the proteins of the ENA/VASP family, which is involved in the formation of cell fibres. These cellular structures, also called actin filaments, fulfil a similar function for the cell to that of the muscles and bones of the human motor apparatus – in other words, they influence its form and mobility and thus processes that also play a key role in the development of metastases.
The active substances currently has the prosaic name "compound 4b", with further versions in the pipeline. Animal experiments are also being prepared at the FMP at present, to test the effect of the substance on tumour metastasis.
Text: Birgit Herden
Opitz R, Müller M, Reuter C, Barone M, Soicke A, Roske Y, Piotukh K, Huy P, Beerbaum M, Wiesner B, Beyermann M, Schmieder P, Freund C, Volkmer R, Oschkinat H, Schmalz HG, Kühne R. A modular toolkit to inhibit proline-rich motif-mediated protein-protein interactions. PNAS 2015 112 (16) 5011-5016. doi:10.1073/pnas.1422054112
The Leibniz-Institut für Molekulare Pharmakologie (FMP) belongs to the Forschungsverbund Berlin e.V. (FVB), a research association comprising eight natural science, life science and environmental science institutes in Berlin, which employ a total of more than 1,500 members of staff. These institutes have received numerous awards for their work and are members of the Leibniz-Gemeinschaft. The research association was founded in 1992 in a unique historical situation from the former Academy of the Sciences of the German Democratic Republic.
Dr. Ronald Kühne
Leibniz-Institut für Molekulare Pharmakologie (FMP)
Tel.: 030 94793 229
Leibniz-Institut für Molekulare Pharmakologie (FMP)
Tel.: 030 94793 104