Bio-inspired foldamers: from catalysis to supramolecular applications

This thesis focuses on the uses of organized foldamers for the development of original catalytic activities. To this aim, a set of different procedures were taken in account and developed by chemical and supramolecular approaches. First, a foldamer-based catalyst is reported as an attractive alternative to the well-developed strategies involving small molecules or conventional peptides. A catalytic foldamer was developed in which a fumaramide chromophore links a Ser residue to a helical domain that contains within its sequence the residues His and Asp. Photoisomerization of the fumaramide chromophore (with E geometry) to the corresponding maleamide (with Z geometry) brings together a ‘catalytic triad’ of Ser, His, and Asp. A detailed conformational study confirmed the helical conformation of the foldamer and the formation of a contact between the two peptide segments. The ability of the foldamer to catalyse the hydrolysis of ester substrates versus control peptides was evaluated and revealed that the fumaramide/maleamide linker thus acts as a light-sensitive switchable cofactor for the in-situ assembly of the catalytic triad of reactive side chains, enabling the photo-control of catalytic activity in short foldamers. A reductive amination approach is reported for the assembly of helical catalytic peptide foldamers containing a -CH2-NH- moiety as replacement of one peptide bond. A detailed ECD, NMR and crystallographic conformational study was performed on (L-Ala-Aib)-based foldamers of increasing length. Over a certain length, the -CH2-NH- moiety is compatible with a fully developed 310/α-helical conformation. This reductive amination approach was then used to synthesize a set of peptide foldamers built, principally from Aib residues, for the creation of catalytic triads. The foldamers were tested in the catalysis of C-C bond macrocyclization of a linear dialdehyde precursor, mediated by primary/secondary amine via imine-enamine chemistry. The high efficiency of the system can be related to the rigid foldamer conformation, which allows spatial control of the relative positioning of the catalytic diads and triads. Various approaches to the synthesis of multivalent hydrolytic catalysts were explored starting from a common peptide sequence containing a ‘catalytic triad’ of Ser, His, and Asp. In a first attempt, the incorporation of a versatile 1,3-dimercaptobenzene core to the peptide sequence was essential to the exploration of dynamic combinatorial libraries to obtain a multivalent catalytic foldamer. Interestingly, the formation of a 16-mer foldamer containing the triad was observed, while the effect of (L-Ala-Aib)4 ordered domains on the composition of the library was also explored. In a second attempt, we investigated the synthesis of silver nanoparticles with a modified p-MBA as ligands to exploit the spatial organization of the ligands in these systems. As the last attempt, we investigated an amphiphilic N-teminal lipidated tetratrapeptide that was able to self-assemble producing a hydrogel with very low concentration of organogelator. The systems obtained with these approaches were compared in the hydrolysis of an activated ester substrate and revealed that silver nanoparticles containing peptide ligands are a promising approach in the development of multivalent peptide-based catalytic systems. Last, the possibility to create self-assembled microstructures with different characteristics and shapes from (L-Ala-Aib)4 based foldamers was explored. A set of amphiphilic peptides were synthesized characterized by polar heads and a common domain which consists in a helicoidal spacer made of an -(L-Ala-Aib)4-octapeptide and N-terminal lipophilic tail. The peptides were able to self-assemble producing different structures, from fibres to liposomal-like structures, depending on the nature of the heads. Co-assembly studies suggested highly efficient recognition phenomena between peptides with different binding heads.This thesis focuses on the uses of organized foldamers for the development of original catalytic activities. To this aim, a set of different procedures were taken in account and developed by chemical and supramolecular approaches. First, a foldamer-based catalyst is reported as an attractive alternative to the well-developed strategies involving small molecules or conventional peptides. A catalytic foldamer was developed in which a fumaramide chromophore links a Ser residue to a helical domain that contains within its sequence the residues His and Asp. Photoisomerization of the fumaramide chromophore (with E geometry) to the corresponding maleamide (with Z geometry) brings together a ‘catalytic triad’ of Ser, His, and Asp. A detailed conformational study confirmed the helical conformation of the foldamer and the formation of a contact between the two peptide segments. The ability of the foldamer to catalyse the hydrolysis of ester substrates versus control peptides was evaluated and revealed that the fumaramide/maleamide linker thus acts as a light-sensitive switchable cofactor for the in-situ assembly of the catalytic triad of reactive side chains, enabling the photo-control of catalytic activity in short foldamers. A reductive amination approach is reported for the assembly of helical catalytic peptide foldamers containing a -CH2-NH- moiety as replacement of one peptide bond. A detailed ECD, NMR and crystallographic conformational study was performed on (L-Ala-Aib)-based foldamers of increasing length. Over a certain length, the -CH2-NH- moiety is compatible with a fully developed 310/α-helical conformation. This reductive amination approach was then used to synthesize a set of peptide foldamers built, principally from Aib residues, for the creation of catalytic triads. The foldamers were tested in the catalysis of C-C bond macrocyclization of a linear dialdehyde precursor, mediated by primary/secondary amine via imine-enamine chemistry. The high efficiency of the system can be related to the rigid foldamer conformation, which allows spatial control of the relative positioning of the catalytic diads and triads. Various approaches to the synthesis of multivalent hydrolytic catalysts were explored starting from a common peptide sequence containing a ‘catalytic triad’ of Ser, His, and Asp. In a first attempt, the incorporation of a versatile 1,3-dimercaptobenzene core to the peptide sequence was essential to the exploration of dynamic combinatorial libraries to obtain a multivalent catalytic foldamer. Interestingly, the formation of a 16-mer foldamer containing the triad was observed, while the effect of (L-Ala-Aib)4 ordered domains on the composition of the library was also explored. In a second attempt, we investigated the synthesis of silver nanoparticles with a modified p-MBA as ligands to exploit the spatial organization of the ligands in these systems. As the last attempt, we investigated an amphiphilic N-teminal lipidated tetratrapeptide that was able to self-assemble producing a hydrogel with very low concentration of organogelator. The systems obtained with these approaches were compared in the hydrolysis of an activated ester substrate and revealed that silver nanoparticles containing peptide ligands are a promising approach in the development of multivalent peptide-based catalytic systems. Last, the possibility to create self-assembled microstructures with different characteristics and shapes from (L-Ala-Aib)4 based foldamers was explored. A set of amphiphilic peptides were synthesized characterized by polar heads and a common domain which consists in a helicoidal spacer made of an -(L-Ala-Aib)4-octapeptide and N-terminal lipophilic tail. The peptides were able to self-assemble producing different structures, from fibres to liposomal-like structures, depending on the nature of the heads. Co-assembly studies suggested highly efficient recognition phenomena between peptides with different binding heads