The Role of the Disulfide Bridge in the Copper (II) Binding by the Cyclic His4-Peptide.

In this paper, we present studies on the influence of the disulfide bridge on the copper (II) ions' binding abilities by the cyclic His4-peptide. The studied ligand HKHPHRHC-S-S-C consists of nine amino acids. The cyclic structure was obtained through a disulfide bridge between two cysteinyl groups. Moreover, this peptide is characterized by the presence of four His residues in the sequence, which makes it an interesting ligand for transition metal ions. The potentiometric and spectroscopic (UV-Vis spectroscopy and circular dichroism spectroscopy (CD)) studies were carried out in various molar ligand to metal ratios: 2:1, 1:1, and 1:2, in the pH range of 2.5-11 at 25 °C. The results showed that the cyclic His4-peptide promotes dinuclear complexes in each of these systems and forms the final dinuclear species with the {NIm, 3N-amide}{NIm, 3N-amide} coordination mode. The obtained data shows that cyclization by the formation of the disulfide bond has an impact on the peptide chain flexibility and appearance of additional potential donors for metal ions and influences the copper (II) ions' coordination.

Detailed Insight into the Interaction of Bicyclic Somatostatin Analogue with Cu(II) Ions.

Somatostatin analogues are useful pharmaceuticals in peptide receptor radionuclide therapy. In previous studies, we analyzed a new bicyclic somatostatin analogue (BCS) in connection with Cu(II) ions. Two characteristic sites were present in the peptide chain: the receptor- and the metal-binding site. We have already shown that this ligand can form very stable imidazole complexes with the metal ion. In this work, our aim was to characterize the intramolecular interaction that occurs in the peptide molecule. Therefore, we analyzed the coordination abilities of two cyclic ligands, i.e., P1 only with the metal binding site and P2 with both sites, but without the disulfide bond. Furthermore, we used magnetic circular dichroism (MCD) spectroscopy to better understand the coordination process. We applied this method to analyze spectra of P1, P2, and BCS, which we have described previously. Additionally, we analyzed the MCD spectra of P3 ligand, which has only the receptor binding site in its structure. We have unequivocally shown that the presence of the Phe-Trp-Lys-Thr motif and the disulfide bond significantly increases the metal binding efficiency.

The Binding Ability of a Bicyclic Somatostatin Analogue Towards Cu(II) Ions.

Somatostatin (SST) analogues have aroused the interest of scientists for years. This group of compounds is used in the diagnosis and treatment of neuroendocrine tumors. However, new molecules useful as radiopharmaceuticals in targeted therapy are still searched for. Bicyclic peptides seem to be very interesting in this context. These molecules are associated with beneficial properties. In this work, we present studies on the binding ability of the bicyclic analogue of somatostatin toward Cu(II) ions which could potentially be a chelator for copper radionuclides. The research is focused on the analysis of Cu(II) interactions with the metal binding cycle of the ligand and the influence of the receptor binding site on the coordination process. This is a novelty in comparison to the SST analogues used in medicine, where a metal ion is coordinated by a chelator and connected with a bioactive molecule by the linker. In this work, we present the first coordination study for a bicyclic ligand. The obtained results showed that the complexes with only imidazole donors are characterized by significantly higher stability in comparison to the other peptides.