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1.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199627

RESUMO

Investigating metal-ion solvation-in particular, the fundamental binding interactions-enhances the understanding of many processes, including hydrogen production via catalysis at metal centers and metal corrosion. Infrared spectra of the hydrated zinc dimer (Zn2+(H2O)n; n = 1-20) were measured in the O-H stretching region, using infrared multiple photon dissociation (IRMPD) spectroscopy. These spectra were then compared with those calculated by using density functional theory. For all cluster sizes, calculated structures adopting asymmetric solvation to one Zn atom in the dimer were found to lie lower in energy than structures adopting symmetric solvation to both Zn atoms. Combining experiment and theory, the spectra show that water molecules preferentially bind to one Zn atom, adopting water binding motifs similar to the Zn+(H2O)n complexes studied previously. A lower coordination number of 2 was observed for Zn2+(H2O)3, evident from the highly red-shifted band in the hydrogen bonding region. Photodissociation leading to loss of a neutral Zn atom was observed only for n = 3, attributed to a particularly low calculated Zn binding energy for this cluster size.


Assuntos
Metais/química , Modelos Moleculares , Água/química , Zinco/química , Cátions/química , Ligação de Hidrogênio , Fótons
2.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065496

RESUMO

The most critical group of all includes multidrug resistant bacteria that pose a particular threat in hospitals, as they can cause severe and often deadly infections. Modern medicine still faces the difficult task of developing new agents for the effective control of bacterial-based diseases. The targeted administration of nanoparticles can enhance the efficiency of conventional pharmaceutical agents. However, the interpretation of interfaces' interactions between nanoparticles and biological systems still remains a challenge for researchers. In fact, the current research presents a strategy for using ZnO NPs immobilization with ampicillin and tetracycline. Firstly, the study provides the mechanism of the ampicillin and tetracycline binding on the surface of ZnO NPs. Secondly, it examines the effect of non-immobilized ZnO NPs, immobilized with ampicillin (ZnONPs/AMP) and tetracycline (ZnONPs/TET), on the cells' metabolism and morphology, based on the protein and lipid profiles. A sorption kinetics study showed that the antibiotics binding on the surface of ZnONPs depend on their structure. The efficiency of the process was definitely higher in the case of ampicillin. In addition, flow cytometry results showed that immobilized nanoparticles present a different mechanism of action. Moreover, according to the MALDI approach, the antibacterial activity mechanism of the investigated ZnO complexes is mainly based on the destruction of cell membrane integrity by lipids and proteins, which is necessary for proper cell function. Additionally, it was noticed that some of the identified changes indicate the activation of defense mechanisms by cells, leading to a decrease in the permeability of a cell's external barriers or the synthesis of repair proteins.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Nanopartículas Metálicas/química , Nanocompostos/química , Zinco/química , Testes de Sensibilidade Microbiana/métodos , Óxido de Zinco/química
3.
Nucleic Acids Res ; 49(11): 6549-6568, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34086935

RESUMO

In mammals, eight aminoacyl-tRNA synthetases (AARSs) and three AARS-interacting multifunctional proteins (AIMPs) form a multi-tRNA synthetase complex (MSC). MSC components possess extension peptides for MSC assembly and specific functions. Human cytosolic methionyl-tRNA synthetase (MRS) has appended peptides at both termini of the catalytic main body. The N-terminal extension includes a glutathione transferase (GST) domain responsible for interacting with AIMP3, and a long linker peptide between the GST and catalytic domains. Herein, we determined crystal structures of the human MRS catalytic main body, and the complex of the GST domain and AIMP3. The structures reveal human-specific structural details of the MRS, and provide a dynamic model for MRS at the level of domain orientation. A movement of zinc knuckles inserted in the catalytic domain is required for MRS catalytic activity. Depending on the position of the GST domain relative to the catalytic main body, MRS can either block or present its tRNA binding site. Since MRS is part of a huge MSC, we propose a dynamic switching between two possible MRS conformations; a closed conformation in which the catalytic domain is compactly attached to the MSC, and an open conformation with a free catalytic domain dissociated from other MSC components.


Assuntos
Metionina tRNA Ligase/química , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Humanos , Modelos Moleculares , Fatores de Alongamento de Peptídeos/química , Peptídeos/química , Conformação Proteica , RNA de Transferência/química , Proteínas Supressoras de Tumor/química , Zinco/química
4.
Food Chem ; 362: 130244, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102510

RESUMO

Rice, consumed by most people across the world, serves as a great mode for carrying nutrients. The processed, starch-rich white rice is mostly devoid of nutrients. High-pressure processing (HPP) is a technology known to produce cold gelatinizing effects in starch. This work shows the application of HPP in fortification of two types of white rice through high pressure gelatinization. The rice grains were impregnated with vitamin B1, calcium, and zinc. HPP treatment was carried out at the temperatures of 50 °C and 70 °C for up to 20 min. The samples were analysed for thiamine using the fluorometric method and minerals using ICP-MS. Results showed that the transfer of nutrients increases with treatment temperature and time, producing high level of nutrient uptake. HPP-fortified rice also showed stability after storage of two months. The moderate-temperature HPP has a great potential to be used as a method to produce a ready-to-eat variety of rice.


Assuntos
Tecnologia de Alimentos/métodos , Temperatura Alta , Micronutrientes/química , Oryza/química , Pressão , Humanos , Micronutrientes/análise , Minerais/química , Amido/química , Tiamina/química , Zinco/química
5.
Food Chem ; 362: 130261, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111691

RESUMO

In this study, a novel surface enhanced Raman spectroscopy (SERS) sensor was developed for the ultrasensitive determination of kanamycin in foods. The sensor used two distinct signal amplification strategies, namely the surface plasmon resonance of gold nanorods and a Zn-doped carbon quantum dots catalytic cascade oxidation-reduction reaction switch controlled by a nucleic acid aptamer. Under optimized experimental conditions, the SERS sensor demonstrated a linear range of 10-12 to 10-5 g mL-1 for the detection of kanamycin, with a limit of detection of 3.03 × 10-13 g mL-1. Experiments with antibiotics structurally similar to kanamycin and interferrants revealed that the sensor had excellent selectivity. Milkpowder and honey samples spiked with kanamycin were assayed, with recoveries ranging from 84.1% to 107.2% and a relative standard deviation of 0.74% to 2.81% being obtained. Quantification of kanamycin in milk samples revealed no significant difference between the results obtained with the sensor and by HPLC.


Assuntos
Aptâmeros de Nucleotídeos/química , Análise de Alimentos/instrumentação , Análise de Alimentos/métodos , Canamicina/análise , Nanotubos/química , Pontos Quânticos/química , Zinco/química , Antibacterianos/análise , Técnicas Biossensoriais/instrumentação , Carbono/química , Catálise , Ouro/química , Limite de Detecção , Nanopartículas Metálicas/química , Análise Espectral Raman/métodos , Ressonância de Plasmônio de Superfície
6.
Nucleic Acids Res ; 49(11): 6511-6528, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34048589

RESUMO

The zinc uptake regulator (Zur) is a member of the Fur (ferric uptake regulator) family transcriptional regulators that plays important roles in zinc homeostasis and virulence of bacteria. Upon zinc perception, Zur binds to the promoters of zinc responsive genes and controls their transcription. However, the mechanism underlying zinc-mediated Zur activation remains unclear. Here we report a 2.2-Å crystal structure of apo Zur from the phytopathogen Xanthomonas campestris pv. campestris (XcZur), which reveals the molecular mechanism that XcZur exists in a closed inactive state before regulatory zinc binding. Subsequently, we present a 1.9-Å crystal structure of holo XcZur, which, by contrast, adopts an open state that has enough capacity to bind DNA. Structural comparison and hydrogen deuterium exchange mass spectrometry (HDX-MS) analyses uncover that binding of a zinc atom in the regulatory site, formed by the hinge region, the dimerization domain and the DNA binding domain, drives a closed-to-open conformational change that is essential for XcZur activation. Moreover, key residues responsible for DNA recognition are identified by site-directed mutagenesis. This work provides important insights into zinc-induced XcZur activation and valuable discussions on the mechanism of DNA recognition.


Assuntos
Proteínas de Bactérias/química , Zinco/química , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Alinhamento de Sequência , Transcrição Genética , Xanthomonas campestris
7.
J Med Chem ; 64(9): 5874-5885, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33945286

RESUMO

Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.


Assuntos
Meios de Contraste/química , Imageamento por Ressonância Magnética , Peroxidase/metabolismo , Animais , Aterosclerose/diagnóstico por imagem , Sítios de Ligação , Cálcio/química , Cálcio/metabolismo , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/metabolismo , Meios de Contraste/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Gadolínio DTPA/química , Gadolínio DTPA/metabolismo , Meia-Vida , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/química , Células RAW 264.7 , Razão Sinal-Ruído , Distribuição Tecidual , Zinco/química , Zinco/metabolismo
8.
Nat Commun ; 12(1): 2646, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976168

RESUMO

Positron Emission Tomography (PET) is a widely-used imaging modality for medical research and clinical diagnosis. Imaging of the radiotracer is obtained from the detected hit positions of the two positron annihilation photons in a detector array. The image is degraded by backgrounds from random coincidences and in-patient scatter events which require correction. In addition to the geometric information, the two annihilation photons are predicted to be produced in a quantum-entangled state, resulting in enhanced correlations between their subsequent interaction processes. To explore this, the predicted entanglement in linear polarisation for the two photons was incorporated into a simulation and tested by comparison with experimental data from a cadmium zinc telluride (CZT) PET demonstrator apparatus. Adapted apparati also enabled correlation measurements where one of the photons had undergone a prior scatter process. We show that the entangled simulation describes the measured correlations and, through simulation of a larger preclinical PET scanner, illustrate a simple method to quantify and remove the unwanted backgrounds in PET using the quantum entanglement information alone.


Assuntos
Algoritmos , Cádmio/química , Modelos Teóricos , Fótons , Tomografia por Emissão de Pósitrons/métodos , Telúrio/química , Zinco/química , Simulação por Computador , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagens de Fantasmas , Tomografia por Emissão de Pósitrons/instrumentação
9.
Int J Mol Sci ; 22(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917615

RESUMO

Patients receiving orthopedic implants are at risk of implant-associated infections (IAI). A growing number of antibiotic-resistant bacteria threaten to hamper the treatment of IAI. The focus has, therefore, shifted towards the development of implants with intrinsic antibacterial activity to prevent the occurrence of infection. The use of Ag, Cu, and Zn has gained momentum as these elements display strong antibacterial behavior and target a wide spectrum of bacteria. In order to incorporate these elements into the surface of titanium-based bone implants, plasma electrolytic oxidation (PEO) has been widely investigated as a single-step process that can biofunctionalize these (highly porous) implant surfaces. Here, we present a systematic review of the studies published between 2009 until 2020 on the biomaterial properties, antibacterial behavior, and biocompatibility of titanium implants biofunctionalized by PEO using Ag, Cu, and Zn. We observed that 100% of surfaces bearing Ag (Ag-surfaces), 93% of surfaces bearing Cu (Cu-surfaces), 73% of surfaces bearing Zn (Zn-surfaces), and 100% of surfaces combining Ag, Cu, and Zn resulted in a significant (i.e., >50%) reduction of bacterial load, while 13% of Ag-surfaces, 10% of Cu-surfaces, and none of Zn or combined Ag, Cu, and Zn surfaces reported cytotoxicity against osteoblasts, stem cells, and immune cells. A majority of the studies investigated the antibacterial activity against S. aureus. Important areas for future research include the biofunctionalization of additively manufactured porous implants and surfaces combining Ag, Cu, and Zn. Furthermore, the antibacterial activity of such implants should be determined in assays focused on prevention, rather than the treatment of IAIs. These implants should be tested using appropriate in vivo bone infection models capable of assessing whether titanium implants biofunctionalized by PEO with Ag, Cu, and Zn can contribute to protect patients against IAI.


Assuntos
Cobre/química , Próteses e Implantes , Prata/química , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/metabolismo , Titânio/química , Zinco/química , Humanos , Osteoblastos/metabolismo , Osteoblastos/patologia , Oxirredução , Porosidade , Infecções Estafilocócicas/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia
10.
Inorg Chem ; 60(8): 5764-5770, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33829775

RESUMO

Two NIR luminescent Zn(II)/Cd(II)-Yb(III) complexes were obtained by the use of a Schiff base ligand with a binaphthyl backbone. Cd(II)-Yb(III) complex 2 has a triangular structure and exhibits interesting luminescent sensing activity to antibiotics, in particular to ciprofloxacin (CPFX) and norfloxacin (NFX) due to the inner filter effect. The limits of the detection of 2 to CPFX and NFX are 0.18 and 0.36 µM, respectively, and the fluorescence sensitivity is not changed with the existence of other antibiotics tested in this study.


Assuntos
Antibacterianos/análise , Cádmio/química , Fluoroquinolonas/análise , Substâncias Luminescentes/química , Itérbio/química , Zinco/química , Raios Infravermelhos , Substâncias Luminescentes/síntese química , Medições Luminescentes , Estrutura Molecular , Bases de Schiff/química
11.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: covidwho-1136500

RESUMO

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.


Assuntos
Antivirais/química , Metais/química , Metisazona/química , Simulação de Acoplamento Molecular , SARS-CoV-2/química , Antivirais/metabolismo , COVID-19/tratamento farmacológico , Cálcio/química , Cálcio/metabolismo , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Desenho de Fármacos , Humanos , Ferro/química , Ferro/metabolismo , Magnésio/química , Magnésio/metabolismo , Manganês/química , Manganês/metabolismo , Metais/metabolismo , Metisazona/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Zinco/química , Zinco/metabolismo
12.
Molecules ; 26(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920742

RESUMO

Excessive UV solar radiation exposure causes human health risks; therefore, the study of multifunctional filters is important to skin UV protective ability and also to other beneficial activities to the human organism, such as reduction of reactive oxygen species (ROS) responsible for cellular damages. Potential multifunctional filters were obtained by intercalating of ferulate anions into layered simple metal hydroxides (LSH) through anion exchange and precipitation at constant pH methods. Ultrasound treatment was used in order to investigate the structural changes in LSH-ferulate materials. Structural and spectroscopic analyses show the formation of layered materials composed by a mixture of LSH intercalated with ferulate anions, where carboxylate groups of ferulate species interact with LSH layers. UV-VIS absorption spectra and in vitro SPF measurements indicate that LSH-ferulate systems have UV shielding capacity, mainly UVB protection. The results of reactive species assays show the ability of layered compounds in capture DPPH•, ABTS•+, ROO•, and HOCl/OCl- reactive species. LSH-ferulate materials exhibit antioxidant activity and singular optical properties that enable their use as multifunctional filters.


Assuntos
Hidróxidos/química , Protetores contra Radiação/química , Raios Ultravioleta/efeitos adversos , Zinco/química , Ânions/química , Antioxidantes/efeitos da radiação , Humanos , Substâncias Intercalantes/química , Metais/química , Espécies Reativas de Oxigênio/química , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Sistema Solar/química , Análise Espectral
13.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921452

RESUMO

The three complexes [Fe(opo)3], [Cu(opo)2], and [Zn(opo)2] containing the non-innocent anionic ligand opo- (opo- = 9-oxido-phenalenone, Hopo = 9-hydroxyphenalonone) were synthesised from the corresponding acetylacetonates. [Zn(opo)2] was characterised using 1H nuclear magnetic resonance (NMR) spectroscopy, the paramagnetic [Fe(opo)3] and [Cu(opo)2] by electron paramagnetic resonance (EPR) spectroscopy. While the EPR spectra of [Cu(opo)2] and [Cu(acac)2] in dimethylformamide (DMF) solution are very similar, a rather narrow spectrum was observed for [Fe(opo)3] in tetrahydrofuran (THF) solution in contrast to the very broad spectrum of [Fe(acac)3] in THF (Hacac = acetylacetone, 2,4-pentanedione; acac- = acetylacetonate). The narrow, completely isotropic signal of [Fe(opo)3] disagrees with a metal-centred S = 5/2 spin system that is observed in the solid state. We assume spin-delocalisation to the opo ligand in the sense of an opo- to FeIII electron transfer. All compounds show several electrochemical opo-centred reduction waves in the range of -1 to -3 V vs. the ferrocene/ferrocenium couple. However, for CuII and FeIII the very first one-electron reductions are metal-centred. Electronic absorption in the UV to vis range are due to π-π* transitions in the opo core, giving Hopo and [Zn(opo)2] a yellow to orange colour. The structured bands ranging from 400 to 500 for all compounds are assigned to the lowest energy π-π* transitions. They show markedly higher intensities and slight shifts for the CuII (brown) and FeIII (red) complexes and we assume admixing metal contributions (MLCT for CuII, LMCT for FeIII). For both complexes long-wavelength absorptions assignable to d-d transitions were detected. Detailed spectroelectrochemical experiments confirm both the electrochemical and the optical assignments. Hopo and the complexes [Cu(opo)2], [Zn(opo)2], and [Fe(opo)3] show antiproliferative activities against HT-29 (colon cancer) and MCF-7 (breast cancer) cell lines in the range of a few µM, comparable to cisplatin under the same conditions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Neoplasias/tratamento farmacológico , Pentanonas/química , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Eletroquímica , Células HT29 , Humanos , Ferro/química , Ligantes , Células MCF-7 , Neoplasias/patologia , Pentanonas/síntese química , Pentanonas/farmacologia , Fenalenos/química , Análise Espectral , Zinco/química
14.
Molecules ; 26(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33804968

RESUMO

Gelatin, a natural polymer, provides excellent tissue compatibility for use in tissue rehabilitation. Bioactive glasses (BAG) offer superior capacity in stimulating a bioactive response but show high variability in uptake and solubility. To tackle these drawbacks, a combination of gelatin with BAG is proposed to form composites, which then offer a synergistic response. The cross-linked gelatin structure's mechanical properties are enhanced by the incorporation of the inorganic BAG, and the rate of BAG ionic supplementation responsible for bioactivity and regenerative potential is better controlled by a protective gelatin layer. Several studies have demonstrated the cellular benefits of these composites in different forms of functional modification such as doping with zinc or incorporation of zinc such as ions directly into the BAG matrix. This review presents a comprehensive perspective on the individual characteristics of BAG and gelatin, including the synthesis and mechanism of action. Further, adaptation of the composite into various applications for bone tissue engineering is discussed and future challenges are highlighted.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Gelatina , Vidro/química , Engenharia Tecidual , Tecidos Suporte/química , Zinco , Animais , Gelatina/química , Gelatina/farmacologia , Humanos , Zinco/química , Zinco/farmacologia
15.
Molecules ; 26(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920893

RESUMO

Herein, we report the synthesis of eight new mononuclear and binuclear Co2+, Ni2+, Cu2+, and Zn2+ methoxy thiosemicarbazone (MTSC) complexes aiming at obtaining thiosemicarbazone complex with potent biological activity. The structure of the MTSC ligand and its metal complexes was fully characterized by elemental analysis, spectroscopic techniques (NMR, FTIR, UV-Vis), molar conductivity, thermogravimetric analysis (TG), and thermal differential analysis (DrTGA). The spectral and analytical data revealed that the obtained thiosemicarbazone-metal complexes have octahedral geometry around the metal center, except for the Zn2+-thiosemicarbazone complexes, which showed a tetrahedral geometry. The antibacterial and antifungal activities of the MTSC ligand and its (Co2+, Ni2+, Cu2+, and Zn2+) metal complexes were also investigated. Interestingly, the antibacterial activity of MTSC- metal complexes against examined bacteria was higher than that of the MTSC alone, which indicates that metal complexation improved the antibacterial activity of the parent ligand. Among different metal complexes, the MTSC- mono- and binuclear Cu2+ complexes showed significant antibacterial activity against Bacillus subtilis and Proteus vulgaris, better than that of the standard gentamycin drug. The in silico molecular docking study has revealed that the MTSC ligand could be a potential inhibitor for the oxidoreductase protein.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Cobalto/química , Cobre/química , Tiossemicarbazonas/química , Zinco/química , Bacillus subtilis/efeitos dos fármacos , Simulação de Acoplamento Molecular , Proteus vulgaris/efeitos dos fármacos , Termogravimetria
16.
Molecules ; 26(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921789

RESUMO

The zinc dithiocarbamates functionalized with folic acid 2Zn and 3Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1Zn). Zinc complexes 2Zn and 3Zn show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes 2Zn or 3Zn and the cation fac-[99mTc(H2O)3(CO)3]+, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[99mTc(CO)3(SS)(P)] bioconjugated to folic acid (2Tc and 3Tc). In spite of the low solubility of 2Zn and 3Zn in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2Re and 3Re) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2Tc and 3Tc indicate low specific binding to folate receptors. In summary, Tc-99m folates 2Tc and 3Tc were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step.


Assuntos
Compostos Orgânicos/química , Compostos Orgânicos/síntese química , Rênio/química , Tecnécio/química , Zinco/química , Ácido Fólico/química , Estrutura Molecular
17.
Molecules ; 26(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800635

RESUMO

The urge for the development of a more efficient antibiotic crystalline forms led us to the disclosure of new antibiotic coordination frameworks of pyrazinamide, a well-known drug used for the treatment of tuberculosis, with some of the novel compounds unravelling improved antimycobacterial activity. Mechanochemistry was the preferred synthetic technique to yield novel compounds, allowing the reproduction of a 1D zinc framework, the synthesis of a novel hydrogen bonding manganese framework, and three new compounds with silver. The structural characterization of the novel forms is presented along with stability studies. The increased antimicrobial activity of the new silver-based frameworks against Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis is particularly relevant.


Assuntos
Antibacterianos/síntese química , Complexos de Coordenação/síntese química , Manganês/química , Compostos Organometálicos/síntese química , Pirazinamida/química , Prata/química , Zinco/química , Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Estabilidade de Medicamentos , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/crescimento & desenvolvimento , Compostos Organometálicos/farmacologia , Pirazinamida/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade
18.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804129

RESUMO

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.


Assuntos
Antivirais/química , Metais/química , Metisazona/química , Simulação de Acoplamento Molecular , SARS-CoV-2/química , Antivirais/metabolismo , COVID-19/tratamento farmacológico , Cálcio/química , Cálcio/metabolismo , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Desenho de Fármacos , Humanos , Ferro/química , Ferro/metabolismo , Magnésio/química , Magnésio/metabolismo , Manganês/química , Manganês/metabolismo , Metais/metabolismo , Metisazona/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Zinco/química , Zinco/metabolismo
19.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799326

RESUMO

The human zinc transporter ZnT8 provides the granules of pancreatic ß-cells with zinc (II) ions for assembly of insulin hexamers for storage. Until recently, the structure and function of human ZnTs have been modelled on the basis of the 3D structures of bacterial zinc exporters, which form homodimers with each monomer having six transmembrane α-helices harbouring the zinc transport site and a cytosolic domain with an α,ß structure and additional zinc-binding sites. However, there are important differences in function as the bacterial proteins export an excess of zinc ions from the bacterial cytoplasm, whereas ZnT8 exports zinc ions into subcellular vesicles when there is no apparent excess of cytosolic zinc ions. Indeed, recent structural investigations of human ZnT8 show differences in metal binding in the cytosolic domain when compared to the bacterial proteins. Two common variants, one with tryptophan (W) and the other with arginine (R) at position 325, have generated considerable interest as the R-variant is associated with a higher risk of developing type 2 diabetes. Since the mutation is at the apex of the cytosolic domain facing towards the cytosol, it is not clear how it can affect zinc transport through the transmembrane domain. We expressed the cytosolic domain of both variants of human ZnT8 and have begun structural and functional studies. We found that (i) the metal binding of the human protein is different from that of the bacterial proteins, (ii) the human protein has a C-terminal extension with three cysteine residues that bind a zinc(II) ion, and (iii) there are small differences in stability between the two variants. In this investigation, we employed nickel(II) ions as a probe for the spectroscopically silent Zn(II) ions and utilised colorimetric and fluorimetric indicators for Ni(II) ions to investigate metal binding. We established Ni(II) coordination to the C-terminal cysteines and found differences in metal affinity and coordination in the two ZnT8 variants. These structural differences are thought to be critical for the functional differences regarding the diabetes risk. Further insight into the assembly of the metal centres in the cytosolic domain was gained from potentiometric investigations of zinc binding to synthetic peptides corresponding to N-terminal and C-terminal sequences of ZnT8 bearing the metal-coordinating ligands. Our work suggests the involvement of the C-terminal cysteines, which are part of the cytosolic domain, in a metal chelation and/or acquisition mechanism and, as now supported by the high-resolution structural work, provides the first example of metal-thiolate coordination chemistry in zinc transporters.


Assuntos
Proteínas de Transporte/ultraestrutura , Insulina/genética , Relação Estrutura-Atividade , Transportador 8 de Zinco/ultraestrutura , Proteínas de Transporte/química , Proteínas de Transporte/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Conformação Molecular , Níquel/química , Conformação Proteica em alfa-Hélice/genética , Domínios Proteicos/genética , Zinco/química , Transportador 8 de Zinco/química , Transportador 8 de Zinco/genética
20.
ACS Appl Mater Interfaces ; 13(13): 15031-15039, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33764744

RESUMO

Enrichment of rare cancer cells from various cell mixtures for subsequent analysis or culture is essential for understanding cancer formation and progression. In particular, maintaining the viability of captured cancer cells and gently releasing them for relevant applications remain challenging for many reported methods. Here, a physically cross-linked deoxyribozyme (DNAzyme)-based hydrogel strategy was developed for the specific envelopment and release of targeted cancer cells, allowing the aptamer-guided capture, 3D envelopment, and Zn2+-dependent release of viable cancer cells. The DNAzyme hydrogel is constructed through the intertwinement and hybridization of two complementary DNAzyme strands located on two rolling circle amplification-synthesized ultralong DNA chains. The enveloping and separation of target cells were achieved during the formation of the DNAzyme hydrogel (sol-gel transition). Triggered by Zn2+, the encapsulated cells can be gently released from the dissociated DNAzyme hydrogel with high viability (gel-sol transition). Successful isolations of target cells from cancer cell mixtures and peripheral blood mononuclear cells (PBMC) were demonstrated. This method offers an attractive approach for the separation of target cancer cells for various downstream applications that require viable cells.


Assuntos
Células Imobilizadas/citologia , DNA Catalítico/química , Hidrogéis/química , Transição de Fase , Aptâmeros de Nucleotídeos/química , Linhagem Celular Tumoral , Células Imobilizadas/química , Humanos , Neoplasias/patologia , Zinco/química
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