Multivalent peptido and glycocalixarenes as ligands for microorganisms

Abstract

The present thesis work deals with the design and synthesis of novel calixarene-based multivalent ligands tailored to interact with proteins exposed on the external membrane of different microorganisms. The calixarene macrocycle was chosen as central core of these multivalent ligands because of the efficient methods known for its selective functionalization either at the upper or lower rims and for the possibility to easily modulate, at will, the geometry of the exposed ligating units. This last feature is particularly important when designing multivalent systems for the recognition of biological macromolecules, since it allows to develop ligands of increased efficiency and selectivity. After a general introduction on calixarenes for protein targeting, the first chapter reports the results of a project aimed at obtaining peptidocalix[4]arenes for the inhibition of the SARS-CoV-2 virus. Our goal was to synthesize ligands able to bind to the virus Spike protein and potentially able to prevent its interaction with its host cell receptor and to block the infection process. This work was triggered by a molecular modelling study to screen in silico potential ligands and was followed by the synthesis of some of the selected compounds and by their tests on a model of the virus. In the second chapter is reported the work performed at the University of Grenoble, where the candidate spent a 6-months research period in the group of prof. Olivier Renaudet. During this period, the attention was focused on the design and synthesis of fucosylated calix[4]arenes for the interaction with three different lectins: Aspergillus fumigatus lectin, Burkholderia ambifaria lectin and LecB from Pseudomonas aeruginosa. In parallel to the synthesis of more classical fucosylated calixarenes, we also synthesized a novel “superstructure” based on a central calix[4]arene core in cone geometry functionalized at the upper rim with four cyclodecapeptides, each of them decorated with four units of fucose, resulting in a peculiar hexadecavalent ligand. All the synthesized compounds were tested in ITC experiments to study their affinity towards the three lectins. Finally, in the last chapter it is described the preparation of calix[4]arene-based ligands designed for the selective recognition of Gram-positive, Gram-negative and Mycobacteria. To develop ligands capable of discriminating among these three bacterial groups we targeted peculiar epitopes or proteins exposed on the surface of their cell wall. The obtainment of selective ligands for each of these classes of bacteria could be an important aid towards the development of new bacterial sensor devices useful, to medical doctors, for the rapid selection of the appropriate antibiotic, preventing the administration of broad-spectrum drugs that are among the main causes of the spread of antibiotic resistance. Moreover, these bacteria ligands could even find applications for the preparation of novel targeted antibacterial drugs.