Maicon Segalla Petrônio

Universidade Estadual Paulista (Unesp)

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Luís Octávio Regasini

Universidade Estadual Paulista (Unesp)

Dulce Helena Siqueira Silva

Universidade Estadual Paulista (Unesp)

Valdecir Farias Ximenes

Universidade Estadual Paulista (Unesp)

Vanderlan da Silva Bolzani

Universidade Estadual Paulista (Unesp)

Márcio José Tiera

Universidade Estadual Paulista (Unesp)

Julio Fernandes

Hôpital du Sacré-Cœur de Montréal

Tamara P. Kondratyuk

University of Hawaii at Hilo

John M. Pezzuto

Baystate Health

Suaib Luqman

Central Institute of Medicinal and Aromatic Plants

Christiane Pienna Soares

Universidade Estadual Paulista (Unesp)

Cooperative Institutions

Universidade Estadual Paulista (Unesp)

Centro Universitário de Araraquara

Universidade de São Paulo

Instituto de Ciências Farmacêuticas

Hôpital du Sacré-Cœur de Montréal

Université de Montréal

Universidade Paulista

Universidade Federal de São Carlos

Brazilian Agricultural Research Corporation

Sorbonne Université

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Alkyl Hydroxybenzoic Acid Derivatives that Inhibit HIV-1 Protease Dimerization

Current Medicinal Chemistry (2012)

Otávio Flausino Laure Dufau Luís Octávio Regasini Maicon Segalla Petrônio Dulce Helena Siqueira Silva

The therapeutic potential of gallic acid and its derivatives as anti-cancer, antimicrobial and antiviral agents is well known. We have examined the mechanism by which natural gallic acid and newly synthesized gallic acid alkyl esters and related protocatechuic acid alkyl esters inhibit HIV-1 protease to compare the influence of the aromatic ring substitutions on inhibition. We used Zhang-Poorman's kinetic analysis and fluorescent probe binding to demonstrate that several gallic and protecatechuic acid alkyl esters inhibited HIV-1 protease by preventing the dimerization of this obligate homodimeric aspartic protease rather than targeting the active site. The tri-hydroxy substituted benzoic moiety in gallates was more favorable than the di-substituted one in protocatechuates. In both series, the type of inhibition, its mechanism and the inhibitory efficiency dramatically depended on the length of the alkyl chain: no inhibition with alkyl chains less than 8 carbon atoms long. Molecular dynamics simulations corroborated the kinetic data and propose that gallic esters are intercalated between the two N- and C-monomer ends. They complete the β-sheet and disrupt the dimeric enzyme. The best gallic ester (14 carbon atoms, Kid of 320 nM) also inhibited the multi-mutated protease MDR-HM. These results will aid the rational design of future generations of non-peptide inhibitors of HIV-1 protease dimerization that inhibit multi-mutated proteases. Finally, our work suggests the wide use of gallic and protocatechuic alkyl esters to dissociate intermolecular β-sheets involved in protein-protein interactions. Keywords: dimerization inhibitors, gallic acid alkyl esters, HIV-1 protease inhibition, intermolecularβ-sheet inhibitors, protocatechuic acid alkyl esters, Alkyl Hydroxybenzoic Acid, fluorescent probe binding, non-peptide inhibitors, protein-protein interactions, aromatic ring substitutions.

Protocatechuic acid

Moiety

10.2174/092986712803251557

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Citations (15)

PO-016 Inhibition of cell proliferation by anti-epidermal growth factor receptor (EGFR) aptamer conjugated chitosan/siRNA nanoparticles

ESMO Open (2018)

Qin Shi Maicon Segalla Petrônio Elsa-Patricia Rondon-Cavanzo M.J. Tiera Mouna Ferdebouh

Introduction Gene silencing mediated by small interfering RNA (siRNA) has been widely investigated as a potential therapeutic approach. Its use, however, is hampered by its rapid degradation and poor cellular uptake into cells. Therefore, the success will depend on the design of effective systems able to selectively and efficiently deliver siRNA to target cells/organs. Our strategy relies on the use of a biocompatible biopolymer (chitosan) as carrier of siRNA coupled with specific anti-EGFR aptamers for cell targeting which is overexpressed in various cancer cells. Finally, poly (ethylene glycol) (PEG) and diethylaminoethyl (DEAE) will be covalently-linked with chitosan, in order to improve blood residency and transfection efficiency. The selected siRNA will be directed to silence receptor activator of nuclear factor-kB ligand (RANKL). Its levels are elevated in numerous cancers. Blockage of EGFR by aptamer and knockdown of RANKL by siRNA inhibit cancer cell proliferation in vitro. Material and methods Synthesise and characterise chitosan conjugates: poly (ethylene glycol) (PEG), diethylaminoethyl (DEAE), and anti-EGFR-aptamer are covalently-linked with chitosan. Synthetize, purify and characterise DEAE/PEG/anti-EGFR-aptamer-chitosan/siRNA nanoparticles Optimise the nanoformulations (adjusting polymeric and charge ratios) through tests in vitro including transfection efficacy and cell proliferation assays in different cancer cell lines. Results and discussions Nanoparticles were produced on the basis of our previous results. Particle size and zeta potential were measured by Zetasizer Nano ZS90 (Malvern Instruments Ltd., Malvern, UK). The sizes of synthesised nanoparticles were around 259±3 nm for Chitosan-DEAE15/siRNA with a zeta potential of +28.3±0.8 mV. The average cell viability of free siRNA or nanoparticle-treated cells was 89%–97% compared to nonrelated cells. The results showed that anti-EGFR-aptamer-chitosan/siRNA nanoparticles had a dose-dependent inhibition of cell proliferation. These nanoparticles had a significant inhibition effect of RANKL mRNA expression (RT-PCR assay. Conclusion Conventional cancer treatments such as chemotherapy have severe side toxicity on both tumour and host cells. Biological targeted agents such as monoclonal antibodies are available, but costly. EGFR and RANKL are two of major targets for drug development for cancer treatment. Non-viral gene therapy involved aptamer-EGFR and siRNA-RANKL is a promising therapy strategy. The supportIng grant was from MESI-Quebec (PSR-SIIRI, 2017–2020).

Aptamer

10.1136/esmoopen-2018-eacr25.551

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Effects of oxidation of lysozyme by hypohalous acids and haloamines on enzymatic activity and aggregation

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (2012)

Maicon Segalla Petrônio Valdecir Farias Ximenes

10.1016/j.bbapap.2012.06.013

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Citations (14)

Apocynin: Chemical and Biophysical Properties of a NADPH Oxidase Inhibitor

Molecules (2013)

Maicon Segalla Petrônio Maria Luiza Zeraik Luiz Fonseca Valdecir Farias Ximenes

Apocynin is the most employed inhibitor of NADPH oxidase (NOX), a multienzymatic complex capable of catalyzing the one-electron reduction of molecular oxygen to the superoxide anion. Despite controversies about its selectivity, apocynin has been used as one of the most promising drugs in experimental models of inflammatory and neurodegenerative diseases. Here, we aimed to study the chemical and biophysical properties of apocynin. The oxidation potential was determined by cyclic voltammetry (Epa = 0.76V), the hydrophobicity index was calculated (logP = 0.83) and the molar absorption coefficient was determined (e275nm = 1.1 × 104 M−1 cm−1). Apocynin was a weak free radical scavenger (as measured using the DPPH, peroxyl radical and nitric oxide assays) when compared to protocatechuic acid, used here as a reference antioxidant. On the other hand, apocynin was more effective than protocatechuic acid as scavenger of the non-radical species hypochlorous acid. Apocynin reacted promptly with the non-radical reactive species H2O2 only in the presence of peroxidase. This finding is relevant, since it represents a new pathway for depleting H2O2 in cellular experimental models, besides the direct inhibition of NADPH oxidase. This could be relevant for its application as an inhibitor of NOX4, since this isoform produces H2O2 and not superoxide anion. The binding parameters calculated by fluorescence quenching showed that apocynin binds to human serum albumin (HSA) with a binding affinity of 2.19 × 104 M−1. The association did not alter the secondary and tertiary structure of HSA, as verified by synchronous fluorescence and circular dichroism. The displacement of fluorescent probes suggested that apocynin binds to site I and site II of HSA. Considering the current biomedical applications of this phytochemical, the dissemination of these chemical and biophysical properties can be very helpful for scientists and physicians interested in the use of apocynin.

Apocynin

Protocatechuic acid

Hypochlorous acid

Protoporphyrin IX

10.3390/molecules18032821

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Citations (135)

Suppression of TNF-α induced NFκB activity by gallic acid and its semi-synthetic alkyl-gallates: Possible role in cancer chemoprevention

Nature Precedings (2012)

Vanderlan da Silva Bolzani Christiane Pienna Soares John M. Pezzuto Suaib Luqman Mauro Batista de Morais

10.1038/npre.2012.6922

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Citations (1)

Inhibitory Effect of Gallic Acid and Its Esters on 2,2′-Azobis(2-amidinopropane)hydrochloride (AAPH)-Induced Hemolysis and Depletion of Intracellular Glutathione in Erythrocytes

Journal of Agricultural and Food Chemistry (2010)

Valdecir Farias Ximenes Mariana G. Lopes Maicon Segalla Petrônio Luís Octávio Regasini Dulce Helena Siqueira Silva

The protective effect of gallic acid and its esters, methyl, propyl, and lauryl gallate, against 2,2'-azobis(2-amidinopropane)hydrochloride (AAPH)-induced hemolysis and depletion of intracellular glutathione (GSH) in erythrocytes was studied. The inhibition of hemolysis was dose-dependent, and the esters were significantly more effective than gallic acid. Gallic acid and its esters were compared with regard to their reactivity to free radicals, using the DPPH and AAPH/pyranine free-cell assays, and no significant difference was obtained. Gallic acid and its esters not only failed to inhibit the depletion of intracellular GSH in erythrocytes induced by AAPH but exacerbated it. Similarly, the oxidation of GSH by AAPH or horseradish peroxidase/H(2)O(2) in cell-free systems was exacerbated by gallic acid or gallates. This property could be involved in the recent findings on pro-apoptotic and pro-oxidant activities of gallates in tumor cells. We provide evidence that lipophilicity and not only radical scavenger potency is an important factor regarding the efficiency of antihemolytic substances.

Hydrochloride

Lipophilicity

Propyl gallate

10.1021/jf100233y

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Citations (57)

Alkyl Caffeates as Anti-Helicobacter Pylori and Scavenger of Oxidants Produced by Neutrophils

Medicinal Chemistry (2013)

Luana Chiquetto Paracatu Cibele Bonacorsi Carolina Quinello Gomes de Farias Ana Carolina Nazaré Maicon Segalla Petrônio

Helicobacter pylori pathogenic action involves the colonization of the gastrointestinal tract and a large production of reactive oxygen species (ROS) by the neutrophils attracted to the site of infection. The aim of this study was to evaluate caffeic acid and its alkyl esters as inhibitors of the release of ROS by Helicobacter pylori activated neutrophils and their bactericidal effect. The increased hydrophobicity caused by esterification had direct consequence in their efficiency as bactericidal agents against H. pylori and inhibitors of the production of ROS by neutrophils. The minimum inhibitory concentration (MIC) decreased from higher than 1000 μg/mL (caffeic acid) to 250 μg/mL to butyl and heptyl caffeate. The release of total ROS, superoxide anion and hypochlorous acid by activated neutrophils was also significantly decreased and the esters were more efficient than the acid precursor. In conclusion, the alkyl esters of caffeic acid have two properties that are complementary for the treatment of H. pylori infections: bactericidal activity and inhibitory effect upon generation of ROS by neutrophils. Hence, we propose that these easily synthesized and non-expensive substances should be applied to in vivo experimental models of H. pylori induced gastric infections. Keywords: Alkyl caffeates, caffeic acid, helicobacter pylori, hypochlorous acid, myeloperoxidase, NADPH-oxidase.

Hypochlorous acid

10.2174/157340641001131226125042

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Citations (10)

Diethylaminoethyl- chitosan as an efficient carrier for siRNA delivery: Improving the condensation process and the nanoparticles properties

International Journal of Biological Macromolecules (2018)

Ricchard Hallan Félix Viegas de Souza Isadora Pfeifer Dalla Picola Qin Shi Maicon Segalla Petrônio Mohamed Benderdour

HeLa

10.1016/j.ijbiomac.2018.07.072

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Citations (40)

Light emission from tryptophan oxidation by hypobromous acid

Luminescence (2012)

Maicon Segalla Petrônio Valdecir Farias Ximenes

ABSTRACT The emission of ultraweak light from cells is a phenomenon associated with the oxidation of biomolecules by reactive oxygen species. The indole moiety present in tryptophan, serotonin and melatonin is frequently associated with the emission of light during the oxidation of these metabolites. This study presents results for hypobromous acid (HOBr) oxidation of tryptophan as a putative endogenous source of ultraweak light emission. We found that chemiluminescence elicited by the oxidation of tryptophan by HOBr was significantly higher than by hypochlorous acid (HOCl). This difference was related to secondary oxidation reactions, which were more intense using HOBr. The products identified during oxidation by HOCl, but depleted by using HOBr, were N ‐formylkynurenine, kynurenine, 1,2,3,3a,8,8a‐hexahydro‐3a‐hydroxypyrrolo[2,3‐b]‐indole‐2‐carboxylic acid, oxindolylalanine and dioxindolylalanine. The emission of light is dependent on the free α‐amino group of tryptophan, and hence, the indole of serotonin and melatonin, although efficiently oxidized, did not produce chemiluminescence. The emission of light was even greater using taurine monobromamine and dibromamine as the oxidant compared to HOBr. A mechanism based on bromine radical intermediates is suggested for the higher efficiency in light emission. Altogether, the experimental evidence described in the present study indicates that the oxidation of free tryptophan or tryptophan residues in proteins is an important source of ultraweak cellular emission of light. This light emission is increased in the presence of taurine, an amino acid present in large amounts in leukocytes, where this putative source of ultraweak light emission is even more relevant. Copyright © 2012 John Wiley & Sons, Ltd.

Light emission

Hypochlorous acid

10.1002/bio.2445

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Citations (11)

Amphipathic chitosans improve the physicochemical properties of siRNA-chitosan nanoparticles at physiological conditions

Carbohydrate Polymers (2019)

Grazieli Olinda Martins Maicon Segalla Petrônio Aline Margarete Furuyama Lima André Miguel Martinez Vera Aparecida de Oliveira Tiera

Chitosan has received a lot of attention as a carrier for small interfering RNA (siRNA), due to its capacity for complexation and intracellular release of these molecules. However, one of its limitations is its insolubility at neutral pH and the tendency towards aggregation of its nanoparticles in isotonic ionic strength. In this study, a series of amphipathic chitosans were synthesized by varying the degree of acetylation (DA) from ˜2 to ˜30 mol% and the degree of substitution (DS) from 5 to 25%. by tertiary amino groups (DEAE) The results showed that the adjustment of these parameters decreases the interparticle interactions mediated by hydrogen bonding to obtain nanoparticles with improved colloidal stability. siRNA-containing nanoparticles of 100 to 150 nm with low polydispersities (0.15–0.2) and slightly positive zeta potentials (˜+ 5 mV) were resistant to aggregation at pH 7.4 and ionic strength of 150 mM. This resistance to aggregation is provided by changes on the nanoparticle surface and highlights the importance of more organized self-assembly in providing colloidal stability at physiological conditions. Additionally, the PEGylation of the most promising vectors conferred favorable physicochemical properties to nanoparticles. The chitosans and their nanoparticles exhibited low toxicity and an efficient cell uptake, as probed by confocal microscopy of rhodamine labeled vectors. The results provide a new approach to overcome the limited stability of chitosan nanoparticles at physiological conditions and show the potential of these amphipathic chitosans as siRNA carriers.

10.1016/j.carbpol.2019.03.098

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Citations (32)