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Introduction: It is recently becoming clear that there is a significant and underestimated effect of metal coordination on the antimicrobial activity of antimicrobial peptides (AMPs) - potential treasure troves for the design of novel antibiotics. Beyond any doubt, understanding the molecular mechanisms underlying these disorders is a serious challenge for modern science. Aim: The way in which metal ions affect the mode of action of AMPs is far from being understood. They may alter the charge/structure/morphology of a given AMP and therefore enhance the AMP antimicrobial potency. The aim of the project is to understand the relationship between metal coordination, thermodynamic stability, structure, morphology and antimicrobial activity of AMPs. Material and methods: Achieving the overall aim requires a complex experimental approach. Mass spectrometry, potentiometry, ITC and a fruitful combination of nMR, UV-Vis, CD and EPR spectroscopic techniques are used to describe the beautiful bioinorganic chemistry of the studied systems. Antimicrobial assays and studies on regular cell lines establish the biological potency of the novel systems. Results: We have recently elucidated the relationship between Zn(II) coordination, structural, morphological change and antifungal activity of human amylin analogues (pramlintide) and for peptides from the shepherin group (from the plant Capsella bursa pastorsis). We observe a logical sequence of phenomena, each of which is the result of the previous one: (i) Zn(II) coordinates to histidyl imidazoles, (ii) causes a structural change of the peptide, which in turn (iii) results in the formation of fibrils. Conclusions: Ultimately, this chain of structural changes has (iv) biological consequences - the Zn(II)-pramlintide and Zn(II)-shepherin complex fibrils have a strong antifungal effect. A similar effect is not observed neither in the case of free ligands, nor in the case of their complexes with Cu(II). A working hypothesis on the mode of action of such Zn(II) complexes assumes that the formed fibrils can act as needles, physically damaging the fungal cell wall or membrane. [ABSTRACT FROM AUTHOR]

Introduction: Undoubtedly, neurodegenerative Diseases (nD) are one of the most serious diseases in modern society. Understanding the molecular mechanisms underlying these disorders is a challenge for global science. nD are still based on huge number of hypothesis, therefore it is important to find out the mechanism which leads to the pathogenic process. Amyloidogenic proteins are associated with severe neurodegenerative disorders afflicting millions of people worldwide. Aim: The misfolding process leading to protein aggregates is far to be completely understood. However, it is well accepted that many factors are able to influence the morphology and kinetics of amyloids formation. The aim of the project is the understanding of the bioinorganic chemistry of biologically significant copper complexes of the amyloidogenic proteins, in the presence of micelles, which mimic the lipid bilayer, to which the proteins are anchored in vivo. Material and methods: Understanding the coordination properties of the metalpeptide complexes will require a complex experimental approach. Mass spectrometry will be used to study the stoichiometry of metal-complex formation. Potentiometry was allow us to determine the thermodynamic parameters. In order to precisely identify the binding sites, the donor atoms and the coordination geometry of complex species formed in solution at given pH, a fruitful combination of nMR, UV-Vis, CD and EPR spectroscopic techniques have been used. Results: The coordination ability of the amyloidogenic fragment of human Prion Protein (hPrP) is significantly different in the aqueous solution when compared to that containing micelles. Our results prove that the metal binding mode strongly depends on the protein backbone structure. The α-helix structuring of the amyloid hPrP domain influences both the metal coordination sphere and the binding affinity. Conclusions: Essential metal ions are actively involved in several biological events associated with neurodegenerative disorders. The molecular understanding basis of the metal homeostasis and regulations in the cells are critical in identifying the underlying causes for diseases pathophysiology, providing proper diagnosis and treatments. It is also necessary for the development of new therapeutic agents able to treat and prevent their occurrence. [ABSTRACT FROM AUTHOR]