Two-armed molecular receptors : peptide recognition and vesicle formation driven by selective non-covalent interactions

Abstract

This thesis presents examples for applying encoded combinatorial chemistry to trace molecular interactions between two-armed receptors and peptidic substrates that could have not been predicted by conventional means. Starting from these selective non-covalent interactions, applications, like supramolecular self-assembly, were investigated in organic and aqueous media. In the first part the synthesis of macrocyclic diketopiperazine receptors and their binding properties towards peptides is described. Combinatorial on-bead studies showed that both macrocyclization of the receptor and choice of the linker-type lead to significant changes in the binding properties compared to their flexible open-chain parent diketopiperazine receptors. Macrocyclization rigidifies the receptor and should induce a higher preorganisation. Thus, the conformations of the macrocyclic receptors were expected to differ from the open-chain diketopiperazine receptor prototype. Binding studies revealed that macrocyclization led not only to lower binding selectivities but also lower affinities toward peptidic guest compared to the open-chain parent receptors. Thus, the flexibility of the open-chain receptor allows the arms to better adjust to a peptidic guest and can be beneficial for selective and higher binding. The second part describes the development of a new class of two-armed receptors consisting of a rigid carbazole backbone and peptidic side-chains which allow for structural as well as functional variations. Compared to the diketopiperazine template, a third functionality is present and allows for attachment of a dye, polymer chain or resin, at the opposite site of the recognition modules. Combinatorial binding studies and solid phase binding assays showed that these carbazole receptors interact with certain tripeptides, in organic solvents, with sequence selectivities and binding affinities that are comparable to those of diketopiperazine receptors. These two-armed receptors have been the basis for the design of receptor libraries to identify selective receptors for interesting peptidic and nonpeptidic substrates. In the third part, selective non-covalent interactions between a diketopiperazine receptor and peptide-PEG conjugates were used to induce the assembly of vesicles in aqueous solution. The vesicles were analysed by a combination of light scattering, electron transmission and atomic force microscopy as well as surface pressure measurements. Vesicle formation was found to be independent of the ratio of receptor to ligand and relies upon selective receptor-peptide interactions. Other peptide-PEG conjugates did not assemble into vesicular structures when mixed with the receptor.