2020/37/N/ST4/03165

2021-2024

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The aim of this project is to synthesize and characterize novel antimicrobial agents with high efficacy against pathogenic microorganisms, based on calcitermin, a natural antibiotic peptide found in human airways. Different classes of mutants will be designed, in order to improve the calcitermin enzymatic stability and biological activity; the physicochemical properties of the most promising products will be deeply investigated, in view of a possible use as treatments against infectious diseases. Thanks to the broad spectrum of activity and scarce attitude to induce antimicrobial resistance, in fact, antimicrobial peptides (AMPs) represent a rational chance to overcome the current drug-resistance crisis and design innovative therapies. One of the major problems related to the AMP-based drugs is their poor proteolytic stability. A commonly accepted strategy to overcome such drawback is to optimize the peptide structure, introducing modifications aimed at improving the resistance to degradation. These novel peptide derivatives (peptidomimetics) can be designed using unnatural occurring building blocks, like D-amino acids, β-amino acids or peptoids. The enzymatic stability must be checked for each peptide derivative together with its antimicrobial properties against the most common pathogens (Gram positive and negative bacteria, fungi). Special attention will be devoted to the SARS-CoV-2 virus, since calcitermin is present in mucous fluid of the human respiratory tract. Such analyses will allow us to choose the most promising novel calcitermin-mutants and corresponding metal complexes. In fact, calcitermin exhibits a better antimicrobial activity in the presence of metal ions.

Finally, this project will focus on how the metals interact with our synthesized molecules, in order to find connections with their biological activity. A broad range of experimental techniques will be employed in order to obtain the thermodynamic parameters of the metal-ligand interaction and to identify the binding sites and the coordination geometry of the formed metal complexes.

We expect to find new peptidomimetics with improved enzymatic stability and promising antimicrobial activity. Modifications of the peptide structure will confer higher proteolytic stability. Furthermore, the ability to interact with metals will be possibly preserved and checked for the new synthesised and most promising peptide derivatives. Taking into account the possibility to find a correlation between biological activity and metal interaction, we are also quite confident to obtain novel classes of antimicrobial agents that will serve as starting material for new therapeutic strategies against infectious diseases.

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