The design of higher order molecular scaffolds with biomedical potential experiences increasing scientific interest. Most often, these individual compounds could already demonstrate bioactivity, i.e. antimicrobial effects. However, when oligomerized, either by self-assembly, or as a combination of more than one molecules by appropriate matching of hydrophobic/polar surfaces, these assemblies could demonstrate alternative effects, with improved biomedical properties. We have recently completed the design of synthetic “foldamer” peptides, which form self-assembled oligomeric scaffolds with dynamic, environment sensitive features. These peptidic assemblies are also able to host/transport hydrophobic compounds as demonstrated by preliminary results on using the lipophilic polyaromatic molecule, pyrene. For this purpose the use of foldamer assemblies is of specific relevance, as these molecules have a much higher stability against degrading enzymes than natural peptides, thus they present long expected activity in in vivo conditions. The developed foldamer sequences, consisting of alternating hydrophilic and hydrophobic residues, can form amphipathic assemblies consisting of a few, molecules, having an apolar interior in aqueous solution. On the basis of this experimental background in our present project we aim to perform a step-by-step modification of the initial foldamer sequence in order to form a small, yet dynamic inner core, which can be suitable for hosting a wider range of hydrophobic drug molecules. Considering the difficulties in foldamer synthesis, we will heavily rely on the infrastructure and expertise of ELTE in peptide synthesis with flow-chemistry. Initially molecular dynamic simulations will be performed on the potential “mutants” in order to select most promising candidates. This is followed by synthesis of the compounds. Once purified, the compounds will be tested for their capacity to host the above small molecules, as well as for properties in both water and in a membrane environment, using i.e NMR spectroscopy, as well as standard techniques in lipid biophysics. Based on these we expect to reach an improved, next generation of sequences, with improved drug hosting capacity, that can establish longer projects with additional experts involved from other important related areas.

Andrea Bodor, Tamás Beke-Somfai, Viktor Farkas

Result_May 2020