Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties.
Magrì. Antonio A; Tabbì. Giovanni G; Giuffrida. Alessandro A; Pappalardo. Giuseppe G; Satriano. Cristina C; Naletova. Irina I; Nicoletti. Vincenzo G VG; Attanasio. Francesco F
Key Findings
- Acetylating Semax alters its copper coordination, creating a CuN3O site with a weaker sulfur interaction.
- The acetylated copper‑Semax complex has a higher (more positive) redox potential and is less stable against reduction by ascorbic acid.
- Acetylation does not improve protection of neuroblastoma cells from copper toxicity; the free N‑terminus is important for cell protection.
- Both Semax and acetylated Semax bind zinc with similar strength and enter cells equally, showing a punctate intracellular distribution.
Practical Outcomes
- For DIY users, acetylating Semax is unlikely to give extra safety or performance benefits related to metal handling. It may even make the peptide more prone to redox changes in the presence of copper. If you are concerned about copper or zinc balance, this study suggests that standard Semax (without acetylation) is not superior for protecting brain cells, and neither form appears to affect zinc uptake.
Summary
Adding an acetyl group to the front of the brain‑boosting peptide Semax changes how it binds copper and zinc. The acetylated version binds copper in a different way, makes the copper‑peptide complex more easily reduced, and does not protect brain cells from copper‑induced damage. Both the normal and acetylated peptides bind zinc similarly and get into cells the same way.
Abstract
Semax is a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) that encompasses the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone and a C-terminal Pro-Gly-Pro tripeptide. N-terminal amino group acetylation (Ac-Semax) modulates the chemical and biological properties of parental peptide, modifying the ability of Semax to form complex species with Cu(II) ion. At physiological pH, the main complex species formed by Ac-Semax, [CuLH<sub>-2</sub>]<sup>2-</sup>, consists in a distorted CuN<sub>3</sub>O chromophore with a weak apical interaction of the methionine sulphur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN<sub>4</sub> chromophore. The reduced ligand field affects the [CuLH<sub>-2</sub>]<sup>2-</sup> formal redox potential, which is more positive than that of Cu(II)-Semax corresponding species. In the amino-free form, the resulting complex species is redox-stable and unreactive against ascorbic acid, unlike the acetylated form. Semax acetylation did not protect from Cu(II) induced toxicity on a SH-SY5Y neuroblastoma cell line, thus demonstrating the crucial role played by the free NH<sub>2</sub> terminus in the cell protection. Since several brain diseases are associated either to Cu(II) or Zn(II) dyshomeostasis, here we characterized also the complex species formed by Zn(II) with Semax and Ac-Semax. Both peptides were able to form Zn(II) complex species with comparable strength. Confocal microscopy imaging confirmed that peptide group acetylation does not affect the Zn(II) influx in neuroblastoma cells. Moreover, a punctuate distribution of Zn(II) within the cells suggests a preferred subcellular localization that might explain the zinc toxic effect. A future perspective can be the use of Ac-Semax as ionophore in antibody drug conjugates to produce a dysmetallostasis in tumor cells.
Study Information
pubmed
2016
2016-08-27T00:00:00.000Z
10.1016/j.jinorgbio.2016.08.013
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