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. 2020 Nov 20;21(22):8794.
doi: 10.3390/ijms21228794.

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

Aleksandra Marciniak  1 , Weronika Witak  1 , Giuseppina Sabatino  2   3 , Anna Maria Papini  2   3 , Justyna Brasuń  1
Affiliations

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

Aleksandra Marciniak et al. Int J Mol Sci. .

Abstract

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.

Keywords: bicyclic peptide; copper(II) complexes; magnetic circular dichroism; potentiometric titration; somatostatin analogues.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of the bicyclic somatostatin analogue (BCS) (c(c(-S-Cys-Phe-Trp-Lys-Thr-Cys-S-)Pro-His-Lys-Lys-His-Pro)) [13] and the three designed peptides that were analyzed: P1. (Ac-c(-S-Cys-Pro-Hisa-Lys-Lys-Hisb-Pro-Cys-S-)-NH2); P2. (c(Ser-Pro-Hisa-Lys-Lys-Hisb-Pro-Ser-Phe-Trp-Lys-Thr); and P3. Ac-c(-S-Cys-Phe-Trp-Lys-Thr-Cys-S)-NH2.
Figure 2
Figure 2
Species distribution curves for the Cu(II)/P1 system in relation to the pH. The ligand concentration was 7 × 10−4 mol/L and pH-metric titration was performed in a 0.3 mol/L KCl solution using sample volumes of 1.5 mL. Measurements were carried out in a 2.5–10 pH range, at 25 °C. The ligand to metal ratio was 2:1.
Figure 3
Figure 3
Spectra for Cu(II)/P1 system: (a) UV-Vis; (b) circular dichroism (CD). The ligand concentration was 7 × 10−4 mol/L and pH-metric titration was performed in a 0.3 mol/L KCl solution using sample volumes of 2 mL. Measurements were carried out in a 2.5–10 pH range, at 25 °C. The pH values were established by adding small amounts of concentrated KOH and HCl solutions. The ligand to metal ratio was 2:1.
Figure 4
Figure 4
(a) Comparison of species distribution curves between Cu(II)/P1 (solid line) and Cu(II)/P2 (dashed line), (b) Comparison of the P1/Cu(II)/P2 systems. The ligands concentrations were 7 × 10−4 mol/L and pH-metric titrations were performed in a 0.3 mol/L KCl solution using sample volumes of 1.5 mL. Measurements were carried out in a 2.5–10 pH range, at 25 °C. The ligand to metal ratio was 2:1.
Figure 5
Figure 5
(a) Comparison of (a) species distribution curves for Cu(II)/P2 (solid line) and Cu(II)/BCS (dashed line) systems in relation to pH; (b) Comparison of the P2/Cu(II)/BCS systems. P2 concentration was 7 × 10−4 mol/L and pH-metric titration was performed in a 0.3 mol/L KCl solution using sample volumes of 1.5 mL. Measurements were carried out in a 2.5–10 pH range, at 25 °C. The ligand to metal ratio was 2:1.
Figure 6
Figure 6
Comparison of CD (solid line) and magnetic circular dichroism (MCD) (dashed line) spectra for: (a) the Cu(II)/P1 system; (b) the Cu(II)/P2 system. The ligand concentrations were 7 × 10−4 mol/L and pH-metric titrations were performed in a 0.3 mol/L KCl solution. Sample volumes were 2.0 mL. The pH values were established by adding small amounts of concentrated KOH and HCl solutions.
Figure 7
Figure 7
pH-dependent MCD spectra of: (a) P3: Ac-c(-S-Cys-Phe-Trp-Lys-Thr-Cys-S)-NH2; (b) P1: Ac-c(-S-Cys-Pro-His-Lys-Lys-His-Pro-Cys-S-)-NH2; (c) P2: c(Ser-Phe-Trp-Lys-Thr-Ser-Pro-His-Lys-Lys-His-Pro); (d) BCS c(c(-S-Cys-Phe-Trp-Lys-Thr-Cys-S)-Pro-His-Lys-Lys-His-Pro). The ligand concentration was 7 × 10−4 mol/L and pH-metric titrations were performed in a 0.3 mol/L KCl solution. Sample volumes were 2.0 mL. The pH values were established by adding small amounts of concentrated KOH and HCl solutions.
Figure 8
Figure 8
pH-dependent MCD corrected spectra of the systems: (a) Cu(II)/P2-P2free; (b) Cu(II)/BCS-BCSfree, (c) Cu(II)/P1-P1free. The ligand concentration was 7 × 10−4 mol/L and pH-metric titrations were performed in a 0.3 mol/L KCl solution. Sample volumes were 2.0 mL. The pH values were established by adding small amounts of concentrated KOH and HCl solutions.
Figure 8
Figure 8
pH-dependent MCD corrected spectra of the systems: (a) Cu(II)/P2-P2free; (b) Cu(II)/BCS-BCSfree, (c) Cu(II)/P1-P1free. The ligand concentration was 7 × 10−4 mol/L and pH-metric titrations were performed in a 0.3 mol/L KCl solution. Sample volumes were 2.0 mL. The pH values were established by adding small amounts of concentrated KOH and HCl solutions.
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