title: 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.
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-2]2-, consists in a distorted CuN3O chromophore with a weak apical interaction of the methionine sulphur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN4chromophore. The reduced ligand field affects the [CuLH-2]2-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 NH2terminus 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.
authors: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy.
authors: Antonio
authors: A
authors: Magrì
authors: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy. Electronic address: giovanni.tabbi@cnr.it.
authors: Giovanni
authors: G
authors: Tabbì
authors: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy.
authors: Alessandro
authors: A
authors: Giuffrida
authors: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy.
authors: Giuseppe
authors: G
authors: Pappalardo
authors: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors: Cristina
authors: C
authors: Satriano
authors: Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy; Consorzio Interuniversitario C.I.R.C.S.M.B., Via C. Ulpiani 27, 70125 Bari, Italy.
authors: Irina
authors: I
authors: Naletova
authors: Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors: Vincenzo G
authors: VG
authors: Nicoletti
authors: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy. Electronic address: francesco.attanasio@cnr.it.
authors: Francesco
authors: F
authors: Attanasio
mesh_terms: D000107:Acetylation; D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007476:Ionophores / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D007476:Ionophores; D010446:Peptide Fragments; D003300:Copper; C048487:ACTH (4-7), Pro-Gly-Pro-; D000324:Adrenocorticotropic Hormone; D015032:Zinc
keywords: Biological activity; Copper; Oxidation; Stability constants; Voltammetry; Zinc