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The relationship between the coordination chemistry and antimicrobial activity of Zn(II) and Cu(II)-bound histatins, salivary antimicrobial peptides, remains enigmatic. We focus on metal complexes of histatin 3 and its two products of hydrolysis: histatin 4 and its N-terminal fragment (histatin 3–4). The thermodynamic stability of these complexes is quite expected – the binding of Cu(II) via the ATCUN motif results in the formation of very stable complexes. In histatin-Zn(II) complexes, the {2Nim} type of coordination dominates, with polymorphic binding sites observed for histatin 3–4 and 5–8, resulting in their low thermodynamic stability compared to the complexes of histatin 3, 4, 5 and 8 with Zn(II), in which we observe a {2Nim, O−} type of coordination. Histatin 3, 3–4 and 4 have greater activity against Gram-positive bacteria than against Gram-negative ones, and Cu(II) or Zn(II) binding can, in some cases, moderately increase the antimicrobial activity of the native histatin 3 and 4, but not the remaining 3–4 fragment. The most probable reason for the metal-enhanced antimicrobial activity is, in this case, a local change of charge, while the chemically fascinating metal binding induced structural changes do not result in a change of biological activity. Neither histatin 3–4, the N-terminal fragment of histatin 3, which remains in solution after cleavage, nor its metal complexes have any antimicrobial activity, but histatin 3–4 presents intriguing Zn(II)-induced structural behavior, changing its secondary structure, with a tendency to form an α-helix. [ABSTRACT FROM AUTHOR]

The main limitation to the use of antimicrobial peptides (AMPs) as regular drugs, against antibiotic and antifungal resistance, mainly relates to their rapid degradation by proteolytic enzymes. The introduction of suitable structural changes in the peptide chain can make the peptide less susceptible to the action of proteases, thus overcoming this problem. To improve the plasma stability of calcitermin, a metal-chelating AMP present in the human respiratory tract and investigated in the present study, C- and/or N- terminal modifications have been introduced in the native sequence. Evaluation of peptide stability has been performed to determine the half-life times in human plasma of both native calcitermin and its derivatives. However, the protection of the peptide termini can also affect its metal coordination behaviour. Thus, the characterization of Zn2+ and Cu2+ complexes has been performed by means of several techniques, including potentiometry, high-resolution mass spectrometry, UV–Vis, circular dichroism and EPR. On the basis of the obtained results, it was possible to compare the biological activity of the studied systems, taking into account both the metal-binding ability and the peptide stability to search for a link among them. A significant result of this study is that the N-terminal protection increases the calcitermin half-life over seven times and the formation of metal complexes confers resistance towards degradation almost doubling its half-life. [ABSTRACT FROM AUTHOR]