Design and characterization of short peptidic sequences mimicking the behavior of larger proteic entities

This thesis deals with the design, synthesis, and applications of short peptidic sequences capable of mimicking some behaviors of larger protein entities. Indeed, peptides can represent the minimalist functional, bioactive portion of a protein, while being more stable, less expensive, and less immunogenic. Besides, peptides have the potential to penetrate further into tissues owing to their smaller size. In the first part of the thesis, peptides have been designed to investigate the interactions between integrins and their protein ligands. we started with a systematic analysis of α4β1 integrin, integrating receptor-ligand interactions of RGD-binding integrins and computational simulations performed with homology or hybrid α4β1 receptors to explain agonism versus antagonism. Subsequently, we constructed a series of LDV-containing cyclopeptides, leading to the identification of several potent ligands against α4 integrins. Computational methods were also employed to elucidate possible models for receptor activation or blockage. Secondly, various nanoplatforms decorated with different integrin-targeting motifs, e.g. LDV- and RGD-based peptides, were prepared, aiming to expand the application of the developed ligands in tumor-targeted therapies. In the third part of the thesis, peptides have been designed to prevent the assembly of a functional protein. This part focuses on synthesizing peptides capable of inhibiting the tetramerization of hLDH 5. As a result, several linear and cyclic peptide inhibitors were identified, demonstrating selective inhibitory efficacy in cancer cells. In the last part, hybrid peptide-phosphate nanocrystals have been validated as mini-enzymes. We explored the in-situ absorption of peptide catalysts using nanocrystalline hydroxyapatite, which serves as an insoluble solid support for peptides recovery. This strategy was validated in the 1,4-conjugate addition of aldehydes to nitrostyrene, resulted in high enantioselectivity.