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1.
J Inorg Biochem ; 213: 111275, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091731

RESUMO

Often, in the search for a highly defined scientific phenomenon, a different one becomes apparent. This was also the case of this work, in the scope of which we planned to search for metal-enhanced, novel antibacterial/antifungal compounds. Instead, we denied the existence of such and revealed the details of the bioinorganic chemistry of Zn(II)-alloferon complexes. Zinc(II) complexes of alloferon 1 and 2, ligands with a sequential difference of one amino acid only, show a substantially different coordination pattern at physiological pH. In the case of Zn(II)-alloferon 1 species, a histamine-like binding mode is observed (N-terminal amine and imidazole of His-1) and the coordination sphere is completed with the imidazole nitrogens of His-6 and His-9; His-12 is not involved in binding. In the case of Zn(II)-alloferon 2, the N-terminal amine and all the three imidazoles present in the sequence participate in the coordination, however, with the chemical shift of His-5 being less affected than those of other imidazoles. The histamine-like binding in Zn(II)-alloferon 1 complex strongly enhances its thermodynamic stability in comparison to the His-1 lacking alloferon 2 analogue. Despite previous reports on the antibacterial and antifungal activity of alloferon 1, no such activity was detected, neither for alloferon 1 and 2 nor for their Zn(II) complexes.


Assuntos
Complexos de Coordenação/química , Peptídeos/química , Zinco/química , Sequência de Aminoácidos , Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Histidina/química , Ligantes , Espectrometria de Massas/métodos , Testes de Sensibilidade Microbiana , Peptídeos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética/métodos , Relação Estrutura-Atividade , Termodinâmica
2.
Inorg Chem ; 59(1): 274-286, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31820933

RESUMO

Tau protein is present in significant amounts in neurons, where it contributes to the stabilization of microtubules. Insoluble neurofibrillary tangles of tau are associated with several neurological disorders known as tauopathies, among which is Alzheimer's disease. In neurons, tau binds tubulin through its microtubule binding domain which comprises four imperfect repeats (R1-R4). The histidine residues contained in these fragments are potential binding sites for metal ions and are located close to the regions that drive the formation of amyloid aggregates of tau. In this study, we present a detailed characterization through potentiometric and spectroscopic methods of the binding of copper in both oxidation states to R1 and R3 peptides, which contain one and two histidine residues, respectively. We also evaluate how the redox cycling of copper bound to tau peptides can mediate oxidation that can potentially target exogenous substrates such as neuronal catecholamines. The resulting quinone oxidation products undergo oligomerization and can competitively give post-translational peptide modifications yielding catechol adducts at amino acid residues. The presence of His-His tandem in the R3 peptide strongly influences both the binding of copper and the reactivity of the resulting copper complex. In particular, the presence of the two adjacent histidines makes the copper(I) binding to R3 much stronger than in R1. The copper-R3 complex is also much more active than the copper-R1 complex in promoting oxidative reactions, indicating that the two neighboring histidines activate copper as a catalyst in molecular oxygen activation reactions.


Assuntos
Complexos de Coordenação/química , Cobre/química , Fragmentos de Peptídeos/química , Proteínas tau/química , Sítios de Ligação , Humanos , Conformação Molecular
3.
Curr Med Chem ; 25(1): 5-21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28462702

RESUMO

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.


Assuntos
Proteínas 14-3-3/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas 14-3-3/química , Proteínas 14-3-3/metabolismo , Humanos , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química
4.
Dalton Trans ; 46(24): 7758-7769, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28589973

RESUMO

Prion proteins (PrP) from different species have the ability to tightly bind Cu2+ ions. Copper coordination sites are located in the disordered and flexible N-terminal region which contains several His anchoring sites. Among them, two His residues are found in the so called amyloidogenic PrP region which is believed to play a key role in the process leading to oligomer and fibril formation. Both chicken and human amyloidogenic regions have a hydrophobic C-terminal region rich in Ala and Val amino acids. Recent findings revealed that this domain undergoes random coil to α-helix structuring upon interaction with membrane models. This interaction might strongly impact metal binding abilities either in terms of donor sets or affinity. In this study we investigated Cu2+ interaction with an amyloidogenic fragment, chPrP105-140, derived from chicken prion protein (chPrP), in different solution environments. The behavior of the peptide and its metal complexes was analyzed in water and in the presence of negative and positive charged membrane mimicking environments formed by sodium dodecyl sulfate (SDS) and dodecyl trimethyl ammonium chloride (DTAC) micelles. The metal coordination sphere, the metal binding affinity and stoichiometry were evaluated by combining spectroscopic and potentiometric methods. Finally we compare copper(ii) interactions with human and chicken amyloidogenic fragments. Our results indicate that the chicken amyloidogenic fragment is a stronger copper ligand than the human amyloidogenic fragment.


Assuntos
Amiloide/química , Cobre/metabolismo , Membranas Artificiais , Fragmentos de Peptídeos/metabolismo , Proteínas Priônicas/química , Sequência de Aminoácidos , Animais , Galinhas , Humanos , Micelas , Modelos Moleculares , Fragmentos de Peptídeos/química , Ligação Proteica/efeitos dos fármacos , Conformação Proteica em alfa-Hélice/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Dodecilsulfato de Sódio/farmacologia , Tensoativos/farmacologia , Termodinâmica
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