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1.
Arch Virol ; 165(6): 1385-1396, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32346764

RESUMO

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3ß-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin) and C11 (3ß-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (ß) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains.


Assuntos
Antivirais/farmacologia , Cardenolídeos/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Antivirais/síntese química , Cardenolídeos/síntese química , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Células Vero
2.
Mikrobiyol Bul ; 54(1): 79-94, 2020 Jan.
Artigo em Turco | MEDLINE | ID: mdl-32050880

RESUMO

While acyclovir, a nucleoside analogue, is widely used for herpes simplex virus type 1 (HSV-1), emergence of drug-resistant viruses due to frequent usage of this class of medicines, and their toxic side effects require exploring novel active molecules. Despite the studies on developing synthetic molecules in medical sciences and pharmacology, herbs as a natural source of biologically-active compounds remain popular. In this in vitro study, olive leaf extract (OLE) and propolis alone or in combination with acyclovir were investigated for their antiviral efficacy in HSV-1.Toxic doses of OLE, propolis, and dimethyl sulfoxide, propolis diluent, for Hep-2 (ATCC, CCL-23) cells were determined by conventional cell culture. Using "endpoint" method, the viral dose infecting half of the cell culture (TCID50) was calculated, and viral quantity was determined with Spearman-Karber method. Antiviral effects of OLE and propolis on HSV-1 were investigated by conventional cell culture and real-time cell analysis (RTCA). Combinations of the two extracts with one another and with acyclovir were evaluated by RTCA. Active substances prepared at three different dilutions were added to tubes with HSV-1 of logTCID50: 11.5 in descending order starting from the highest non-toxic concentration, and they were left at room temperature for two different durations (one hour and three hours). The aliquots taken from the tubes were cultured in plates containing Hep-2 cells and evaluated after 72 hours. Combinations of extracts and acyclovir at concentrations at least four times lower than the lowest concentration showing antiviral efficacy against HSV-1 were cultured with Hep-2 cells in the e-plates of the xCELLigence RTCA device, measurements were obtained at 30 minute intervals, and data were recorded in real time. In the test with two different durations and at different concentrations of OLE and propolis, antiviral efficacy was observed both with one-hour and three-hour incubation at a concentration of 10 µg/ ml for propolis and 1.2 mg/ml for OLE with RTCA. The duration and concentration of the greatest decrease in viral quantity were in the first one hour and 10 µg/ml for propolis, and in the first one hour and 1.2 mg/ ml for OLE. Combination of propolis and OLE with acyclovir caused no cytopathic effects, and the combination of extracts led to delayed cytopathic effect. According to these results, propolis and OLE, alone and in combinations with acyclovir, have antiviral efficacy against HSV-1. These agents may reduce the dose and side effects of acyclovir in case of co-administration since they exert their effects through a different mechanism than acyclovir,possibly through direct virucidal activity, inhibition of virus internalization or viral inhibition in early stages of replication (inhibition of adsorption/binding of viral particles to the cell). These extracts that do not require conversion to active form have the potential to reduce infectivity in oral lesions, prevent spread, and be used in the topical treatment of acyclovir-resistant HSV infections, particularly in immunocompromised patients. However, in vivo studies should be conducted to determine their medicinal properties and potential toxicities. These results should be supported by further comprehensive studies and the efficacy against other viruses should also be investigated.


Assuntos
Aciclovir , Antivirais , Herpesvirus Humano 1 , Olea , Extratos Vegetais , Própole , Aciclovir/farmacologia , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Olea/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Própole/farmacologia
3.
Phytochemistry ; 171: 112229, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901474

RESUMO

Seven undescribed cycloartane triterpenoids, pseudolarnoids A-G, together with ten known ones, were isolated from the seeds of Pseudolarix amabilis (J. Nelson) Rehder. Their structures were elucidated on the basis of spectroscopic analysis, X-ray crystallography, and ECD data. Pseudolarnoids A-C are cycloartane triterpenoids with a unique 16S, 23R-spirolactone moiety. Pseudolarnoids F, G, and pseudolarolide C demonstrated potent antiviral effects on HSV-1 in vitro.


Assuntos
Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Triterpenos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Pinaceae/química , Triterpenos/química , Triterpenos/isolamento & purificação
4.
Carbohydr Polym ; 229: 115487, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826428

RESUMO

Purified fucoidans SHAP-1 and SHAP-2 with apparent molecular weights of 6.55 × 105 and 5.89 × 105, respectively, were isolated from Sargassum henslowianum by ion-exchange and gel-filtration column chromatography. They are both composed of fucose and galactose at a ratio of around 3:1 and 31.9% sulfate. The backbone of two fucoidans consists of α-(1→3)-linked L-Fucp residues which are mainly sulfated on the C-2 and C-4 positions. Side chains composed of terminally linked α-L-Fucp and α-D-Galp residues, and (1→2)-, (1→6)-, and (1→2,6)-linked ß-D-Galp residues attach mainly at O-4 position of backbone residues. Antiviral test showed that the IC50 values of SHAP-1 and SHAP-2 against HSV-1 were estimated to be 0.89 and 0.82 µg/mL by plaque reduction assay, respectively, whereas both as low as 0.48 µg/mL against HSV-2. The antiviral mechanism of the fucoidans might be at least through blocking HSV-2 virion adsorption to host cells. These results suggest that the fucoidans have potential clinical applications.


Assuntos
Antivirais/química , Antivirais/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Sargassum/química , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos
5.
Microbiol Immunol ; 63(9): 359-366, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301156

RESUMO

Umesu phenolics were obtained from the salt extracts of Japanese apricot (Nanko-mume cultivar of Prunus mume Sieb. et Zucc.) as purified phenolics. The antiviral activities of umesu phenolics obtained were then examined against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), enveloped DNA viruses. The phenolics inhibited the multiplication of these viruses when added to the culture media of the infected cells. This inhibition occurred at phenolic concentrations at which they showed no severe cytotoxicity. One-step growth experiments showed that the eclipse period in the HSV-1 multiplication process was extended in the presence of umesu phenolics and that the addition of phenolics after the completion of viral DNA replication did not affect their multiplication. More drastic effects were observed on virucidal activities against HSV-1 and HSV-2; the infectivity decreased to 0.0001 when infected cells were incubated with 3 mg/ml phenolics at 30°C for 5 min. These results demonstrate the antiviral and virucidal activities of umesu phenolics and suggest a potential pharmacological use for these phenolics as a sanitizing or preventive medicine against superficial HSV infections.


Assuntos
Herpes Simples/tratamento farmacológico , Extratos Vegetais/farmacologia , Prunus armeniaca/química , Simplexvirus/efeitos dos fármacos , Animais , Antivirais/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Replicação do DNA/efeitos dos fármacos , Vírus de DNA/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/crescimento & desenvolvimento , Humanos , Japão , Simplexvirus/crescimento & desenvolvimento , Células Vero , Ligação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
6.
Int J Biol Macromol ; 136: 521-530, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158418

RESUMO

The provisioning of compound libraries with a high degree of diversity and attractive pharmacological properties is a limiting step in drug development. This study reports the production of highly bioactive sulfated polysaccharides, originally present in a nonsulfated, dormant state in natural sources, and demonstrates their antiviral activity (human cytomegalovirus EC50 values of 2.34-7.77 µg/mL) at a low degree of cytotoxicity. Furthermore, data strongly suggested the inhibition of virus entry as the main mode of antiviral action. Remarkably, the utilized oleum-DMF reagent was able to generate a range of sulfated polysaccharides from various natural sources, possessing varying saccharide compositions, degrees of sulfation (0.4-1.7) and molecular masses (38-94,000 g/mol). Typically, in a matter of minutes, this reagent not only solubilized polysaccharides but also chemically converted their hydroxyl functionality into sulfates. The most active sulfated polysaccharide (EC50 of 2.62 µg/mL) proved to be a 94,000 g/mol branched glucan with sulfates at C-6/C-3,6/C-2,3,6 positions. In conclusion, the important determinants of such compounds' antiviral activity are: (i) degree of sulfation, (ii) molecular mass and (iii) structural features. Thus, our approach offers a huge prospect for the improvement of natural source-derived libraries based on biologically active polysaccharides with diversified chemical profiles.


Assuntos
Antivirais/química , Antivirais/farmacologia , Produtos Biológicos/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Sulfatos/química , Antivirais/isolamento & purificação , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Glicosilação , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Humanos , Peso Molecular , Plantas/química , Polissacarídeos/isolamento & purificação , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
7.
Int J Biol Macromol ; 137: 54-61, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226380

RESUMO

Azadirachta indica leaf is used by Indian population for the healing of various diseases including viral infection. Herein, we analyzed the antiherpetic (HSV-1) activity of two polysaccharides (P1 and P2) isolated from the leaf of A. indica and their chemically sulfated derivatives (P1S and P2S). The molecular weights of P1S and P2S are 41 and 11 kDa, respectively. Sulfate groups are located at positions C3 of the Araf and C6 of both Galp and Glcp residues of the most active polysaccharide (P1S). These compounds were not cytotoxic in HEp-2 cells, up to 1000 µg/mL. Both P1S and P2S exhibited antiviral activity when used simultaneously to HSV-1, with 50% inhibitory concentration/selectivity index, respectively, of 31.1 µg/mL/>51.4 and 80.5 µg/mL/>19.8. P1S showed better inhibitory effect (91.8%) compared to P1 (50%), P2 (71.1%) and P2S (70%) at 200 µg/mL. Synthesis of viral protein showed a dose-dependent response and the nucleic acid synthesis was inhibited up to 25 µg/mL, by P1 and P1S and up to 50 µg/mL, by P2 and P2S. The antiviral effect is probably due to the interference of polysaccharides at the early stages of HSV-1 replication, including adsorption. Further studies are under way to get insight into the mechanism of action of the substances.


Assuntos
Antivirais/química , Antivirais/farmacologia , Azadirachta/química , Herpesvirus Humano 1/efeitos dos fármacos , Polissacarídeos/química , Polissacarídeos/farmacologia , Sulfatos/química , Linhagem Celular Tumoral , Herpesvirus Humano 1/fisiologia , Humanos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
8.
mBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088925

RESUMO

Viruses commandeer host cell 26S proteasome activity to promote viral entry, gene expression, replication, assembly, and egress. Proteasomal degradation activity is critical for herpes simplex virus (HSV) infection. The proteasome inhibitor bortezomib (also known as Velcade and PS-341) is a clinically effective antineoplastic drug that is FDA approved for treatment of hematologic malignancies such as multiple myeloma and mantle cell lymphoma. Low nanomolar concentrations of bortezomib inhibited infection by HSV-1, HSV-2, and acyclovir-resistant strains. Inhibition coincided with minimal cytotoxicity. Bortezomib did not affect attachment of HSV to cells or inactivate the virus directly. Bortezomib acted early in HSV infection by perturbing two distinct proteasome-dependent steps that occur within the initial hours of infection: the transport of incoming viral nucleocapsids to the nucleus and the virus-induced disruption of host nuclear domain 10 (ND10) structures. The combination of bortezomib with acyclovir demonstrated synergistic inhibitory effects on HSV infection. Thus, bortezomib is a novel potential therapeutic for HSV with a defined mechanism of action.IMPORTANCE Viruses usurp host cell functions to advance their replicative agenda. HSV relies on cellular proteasome activity for successful infection. Proteasome inhibitors, such as MG132, block HSV infection at multiple stages of the infectious cycle. Targeting host cell processes for antiviral intervention is an unconventional approach that might limit antiviral resistance. Here we demonstrated that the proteasome inhibitor bortezomib, which is a clinically effective cancer drug, has the in vitro features of a promising anti-HSV therapeutic. Bortezomib inhibited HSV infection during the first hours of infection at nanomolar concentrations that were minimally cytotoxic. The mechanism of bortezomib's inhibition of early HSV infection was to halt nucleocapsid transport to the nucleus and to stabilize the ND10 cellular defense complex. Bortezomib and acyclovir acted synergistically to inhibit HSV infection. Overall, we present evidence for the repurposing of bortezomib as a novel antiherpesviral agent and describe specific mechanisms of action.


Assuntos
Antivirais/farmacologia , Bortezomib/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Internalização do Vírus/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Núcleo Celular/metabolismo , Sinergismo Farmacológico , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Prepúcio do Pênis/citologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/fisiologia , Humanos , Masculino , Nucleocapsídeo/metabolismo , Células Vero
9.
Biol Pharm Bull ; 42(5): 833-836, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061327

RESUMO

Derivatives of C2-symmetrical bivalent phenylboronic acid exhibit several remarkable biological activities such as anti-herpes simplex virus (HSV)-1 and cytotoxic activities against Vero cells and they can reverse the effect of anticancer drugs. Novel symmetrical bivalent molecules were synthesized and their biological activities were evaluated in vitro using a human brain glioma cell line (U251) and a human carcinoma cell line (KB3-1). Among the tested compounds (1a-i), bivalent C2-symmetrical phenylboronic acid derivative 1g showed the highest anti-proliferative activity towards both U251 and KB3-1 cells. The values of 50% anti-proliferative activity (IC50) of this compound against the two cell lines (U251 and KB3-1) were 19.0 and 3.78 µM, respectively. The anti-proliferative activity of compound 1g towards KB3-1 cells was higher than that of cisplatin. The bivalent C2-symmetrical compound 1g had a linear methylene linker in the molecule.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Ácidos Borônicos/farmacologia , Animais , Neoplasias Encefálicas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glioma , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Células Vero
10.
Carbohydr Res ; 478: 18-24, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048118

RESUMO

The brown seaweed Scytosiphon lomentaria produces moderate amounts of fucoidans. By cetrimide fractionation, typical heavily sulfated galactofucans are obtained, with no major signs of chemical heterogeneity, together with fractions with higher proportions of xylose, mannose and uronic acids. Anyway, fucose is the most important monosaccharide in most of the subfractions of the subsequent extracts. The fucan moieties appear to be mostly as 3-linked α-l-fucopyranosyl units, with several patterns of sulfate and branching. Galactose is mostly 6-linked, whereas mannose appears to be 2-linked, and xylose appears mostly as terminal stubs. Small amounts of 2-O-acetylated fucose units appear. A high and selective antiviral activity against HSV-1 and HSV-2 was determined for the galactofucan fractions whereas the uronofucoidans were inactive.


Assuntos
Antivirais/farmacologia , Fucose/farmacologia , Galactose/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Polissacarídeos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Configuração de Carboidratos , Fucose/química , Fucose/isolamento & purificação , Galactose/química , Galactose/isolamento & purificação , Testes de Sensibilidade Microbiana , Feófitas/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificação
11.
Prep Biochem Biotechnol ; 49(7): 686-694, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31035907

RESUMO

In mammalian cell culture technology, viral contamination is one of the main challenges; and, so far, various strategies have been taken to remove or inactivate viruses in the cell-line production process. The suitability and feasibility of each method are determined by different factors including effectiveness in target virus inactivation, maintaining recombinant protein stability, easiness-in terms of the process condition, cost-effectiveness, and eco-friendliness. In this research, Taguchi design-of-experiments (DOE) methodology was used to optimize a non-detergent viral inactivation method via considering four factors of temperature, time, pH, and alcohol concentration in an unbiased (orthogonal) fashion with low influence of nuisance factors. Herpes Simplex Virus-1 (HSV1) and Vero cell-line were used as models for enveloped viruses and cell-line, respectively. Examining the cytopathic effects (CPE) in different dilutions showed that pH (4), alcohol (15%), time (120 min), and temperature (25 °C) were the optimal points for viral inactivation. Evaluating the significance of each parameter in the HSV-1 inactivation using Taguchi and ANOVA analyses, the contributions of pH, alcohol, temperature and time were 56.5%, 19.2%, 12%, and 12%, respectively. Examining the impact of the optimal viral treatment condition on the stability of model recombinant protein-recombinant human erythropoietin, no destabilization was detected.


Assuntos
Técnicas de Cultura de Células/métodos , Herpesvirus Humano 1/fisiologia , Inativação de Vírus , Álcoois/metabolismo , Animais , Técnicas de Cultura de Células/instrumentação , Desenho de Equipamento , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Projetos de Pesquisa , Temperatura , Células Vero , Ensaio de Placa Viral , Inativação de Vírus/efeitos dos fármacos
12.
Mar Drugs ; 17(4)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978942

RESUMO

The emergence of antibiotic resistance and viruses with high epidemic potential made unexplored marine environments an appealing target source for new metabolites. Marine fungi represent one of the most suitable sources for the discovery of new compounds. Thus, the aim of this work was (i) to isolate and identify fungi associated with the Atlantic sponge Grantia compressa; (ii) to study the fungal metabolites by applying the OSMAC approach (one strain; many compounds); (iii) to test fungal compounds for their antimicrobial activities. Twenty-one fungal strains (17 taxa) were isolated from G. compressa. The OSMAC approach revealed an astonishing metabolic diversity in the marine fungus Eurotium chevalieri MUT 2316, from which 10 compounds were extracted, isolated, and characterized. All metabolites were tested against viruses and bacteria (reference and multidrug-resistant strains). Dihydroauroglaucin completely inhibited the replication of influenza A virus; as for herpes simplex virus 1, total inhibition of replication was observed for both physcion and neoechinulin D. Six out of 10 compounds were active against Gram-positive bacteria with isodihydroauroglaucin being the most promising compound (minimal inhibitory concentration (MIC) 4-64 µg/mL) with bactericidal activity. Overall, G. compressa proved to be an outstanding source of fungal diversity. Marine fungi were capable of producing different metabolites; in particular, the compounds isolated from E. chevalieri showed promising bioactivity against well-known and emerging pathogens.


Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , Biotecnologia/métodos , Eurotium/metabolismo , Poríferos/microbiologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antivirais/química , Antivirais/isolamento & purificação , Organismos Aquáticos/genética , Organismos Aquáticos/isolamento & purificação , Organismos Aquáticos/metabolismo , Biodiversidade , Cães , Eurotium/genética , Eurotium/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Células Vero , Replicação Viral/efeitos dos fármacos
13.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986933

RESUMO

Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus (HHV) type 1 and 2, and Dengue virus serotype 2 (DENV-2). The cytotoxicity on HeLa and Jurkat tumor cell lines was also tested. Using plaque forming unit assays, cell viability assays and molecular docking, we found that NQ 4 was the best antiviral compound, while AQ 11 was the most active and selective molecule on the tested tumor cells. NQ 4 showed a fair antiviral activity against Herpesviruses (EC50: <0.4 µg/mL, <1.28 µM) and DENV-2 (1.6 µg/mL, 5.1 µM) on pre-infective stages. Additionally, NQ 4 disrupted the viral attachment of HHV-1 to Vero cells (EC50: 0.12 µg/mL, 0.38 µM) with a very high selectivity index (SI = 1728). The in silico analysis predicted that this quinone could bind to the prefusion form of the E glycoprotein of DENV-2. These findings demonstrate that NQ 4 is a potent and highly selective antiviral compound, while suggesting its ability to prevent Herpes and Dengue infections. Additionally, AQ 11 can be considered of interest as a leader for the design of new anticancer agents.


Assuntos
Antraquinonas/química , Antivirais/química , Antivirais/farmacologia , Naftoquinonas/química , Animais , Linhagem Celular Tumoral , Vírus da Dengue/efeitos dos fármacos , Células HeLa , Herpesviridae/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Estrutura Molecular , Células Vero
14.
Oxid Med Cell Longev ; 2019: 2302835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886672

RESUMO

Herpes simplex virus type 1 (HSV-1) has the ability to replicate in neurons and glial cells and to produce encephalitis leading to neurodegeneration. Accumulated evidence suggests that nitric oxide (NO) is a key molecule in the pathogenesis of neurotropic virus infections. NO can exert both cytoprotective as well as cytotoxic effects in the central nervous system (CNS) depending on its concentration, time course exposure, and site of action. In this study, we used an in vitro model of HSV-1-infected primary neuronal and mixed glial cultures as well as an intranasal model of HSV-1 in BALB/c mice to elucidate the role of NO and nonapoptotic Fas signalling in neuroinflammation and neurodegeneration. We found that low, nontoxic concentration of NO decreased HSV-1 replication in neuronal cultures together with production of IFN-alpha and proinflammatory chemokines. However, in HSV-1-infected glial cultures, low concentrations of NO supported virus replication and production of IFN-alpha and proinflammatory chemokines. HSV-1-infected microglia downregulated Fas expression and upregulated its ligand, FasL. Fas signalling led to production of proinflammatory cytokines and chemokines as well as induced iNOS in uninfected bystander glial cells. On the contrary, NO reduced production of IFN-alpha and CXCL10 through nonapoptotic Fas signalling in HSV-1-infected neuronal cultures. Here, we also observed colocalization of NO production with the accumulation of ß-amyloid peptide in HSV-1-infected neurons both in vitro and in vivo. Low levels of the NO donor increased accumulation of ß-amyloid in uninfected primary neuronal cultures, while the NO inhibitor decreased its accumulation in HSV-1-infected neuronal cultures. This study shows for the first time the existence of a link between NO and Fas signalling during HSV-1-induced neuroinflammation and neurodegeneration.


Assuntos
Herpesvirus Humano 1/fisiologia , Inflamação/virologia , Neurônios/patologia , Neurônios/virologia , Óxido Nítrico/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Quimiocinas , Proteína Ligante Fas/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos , Receptor fas/metabolismo
15.
Virol Sin ; 34(3): 315-323, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30915606

RESUMO

Honokiol is a pleiotropic natural compound isolated from Magnolia and has multiple biological and clinically relevant effects, including anticancer and antimicrobial function. However, the antiviral activity of honokiol has not yet been well studied. Here we showed that honokiol had no effect on herpes simplex virus-1 (HSV-1) entry, but inhibited HSV-1 viral DNA replication, gene expression and the production of new progeny viruses. The combination of honokiol and clinical drug acyclovir augmented inhibition of HSV-1 infection. Our results illustrate that honokiol could be a potential new candidate for clinical consideration in the treatment of HSV-1 infection alone or combination with other therapeutics.


Assuntos
Antivirais/farmacologia , Compostos de Bifenilo/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Lignanas/farmacologia , Replicação Viral/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Replicação do DNA , Genoma Viral , Herpesvirus Humano 1/fisiologia , Magnolia/química , Camundongos , Camundongos Endogâmicos C57BL , Compostos Fitoquímicos/farmacologia , Células Vero
16.
Curr Pharm Biotechnol ; 20(3): 215-221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30848197

RESUMO

BACKGROUND: Herpes simplex virus (HSV) and poliovirus (PV) are both agents of major concern in the public health system. It has been shown that Dimorphandra gardneriana galactomannans can be used as solubilizer vehicles in the manufacturing of medicine. Mangiferin is the major constituent of Mangifera indica and presents multiple medicinal and biological activities. OBJECTIVE: This study assayed the effect of D. gardneriana galactomannan combined with mangiferin (DgGmM) against HSV-1 and PV-1. METHODS: The DgGmM cytotoxicity was evaluated by the colorimetric MTT method and the antiviral activity by plaque reduction assay, immunofluorescence and polymerase chain reaction (PCR), in HEp-2 cells. RESULTS: The DgGmM showed a 50% cytotoxic concentration (CC50) > 2000 µg/mL. The 50% inhibitory concentrations (IC50) for HSV-1 and PV-1 were, respectively, 287.5 µg/mL and 206.2 µg/mL, with selectivity indexes (SI) > 6.95 for the former and > 9.69 for the latter. The DgGmM time-ofaddition protocol for HSV-1 showed a maximum inhibition at 500 µg/mL, when added concomitantly to infection and at the time 1 h post-infection (pi). While for PV-1, for the same protocol, the greatest inhibition, was also observed concomitantly to infection at 500 µg/mL and at the times 4 h and 8 h pi. The inhibition was also demonstrated by the decrease of fluorescent cells and/or the inhibition of specific viral genome. CONCLUSION: These results suggested that the DgGmM inhibited HSV-1 and PV-1 replication, with low cytotoxicity and high selectivity and, therefore, represents a potential candidate for further studies on the control of herpes and polio infections.


Assuntos
Antivirais/administração & dosagem , Herpesvirus Humano 1/efeitos dos fármacos , Mananas/administração & dosagem , Extratos Vegetais/administração & dosagem , Xantonas/administração & dosagem , Antivirais/isolamento & purificação , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Células Hep G2 , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/fisiologia , Humanos , Mananas/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Poliovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Replicação Viral/fisiologia , Xantonas/isolamento & purificação
17.
Arch Virol ; 164(5): 1259-1269, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30903291

RESUMO

The long-term administration of acyclovir (ACV) for therapy against herpes simplex virus type 1 (HSV-1) infections can result in the emergence of ACV-resistant HSV strains. It is therefore urgent to develop new anti-herpetic compounds with mechanisms that differ from that of ACV. Cyanovirin-N (CV-N) is an antiviral agent that has an inhibitory effect on HSV-1 infections, and PEGylation of CV-N is potentially useful for pharmaceutical applications. Here, a (Gly4Ser)3 linker molecule was attached to the N-terminus of CV-N, and the resulting compound, linker-CV-N (LCV-N), was produced on a pilot scale with purity up to 95%. Then, PEG10k-LCV-N was synthesized by modifying at the α-amine group of the N-terminus of LCV-N with 10-kDa polyethylene glycol propionaldehyde (mPEG-ALD). CV-N, LCV-N and PEG10k-LCV-N were all found to have potent inhibitory activity against ACV-resistant HSV strains with IC50 values in the nM range. LCV-N was the most potent of these three compounds against both normal and ACV-resistant HSV strains. Although PEG10k-LCV-N showed less antiviral activity than CV-N and LCV-N, it still exhibited significant and universal virucidal activity against drug-resistant viruses. The toxicity and immunogenicity of PEG10k-LCV-N were dramatically lower than those of CV-N and LCV-N. In conclusion, we suggest that LCV-N and PEG10k-LCV-N are promising and safe microbicides for the control and/or treatment of ACV-resistant HSV infection.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/uso terapêutico , Proteínas de Transporte/química , Proteínas de Transporte/uso terapêutico , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Polietilenoglicóis/química , Aciclovir/farmacologia , Animais , Proteínas de Bactérias/síntese química , Proteínas de Transporte/síntese química , Linhagem Celular , Farmacorresistência Viral/genética , Feminino , Herpesvirus Humano 1/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Células Vero
18.
Eur J Pharm Sci ; 132: 34-43, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30807815

RESUMO

The present study was aimed at broadening the profile of toxicity and biological activity of promising fused azaisocytosine-containing congeners (I-VI) possessing medical applicability and important pharmacokinetic properties. For this purpose, the in vivo zebrafish test was applied for evaluating embryotoxic effects of test compounds, whereas the ex vivo model of oxidatively-stressed rat erythrocytes was developed for assessing their antihaemolytic activities. Additionally, the MTT-based assays suitable for assessing cytotoxic and antiviral activities of I-VI were employed. The influence of compounds I-VI on zebrafish embryos/larvae was carefully investigated in relation to lack or presence of various substituents at the phenyl moiety. The least embryotoxic proved to be the parent compound (I) and its para-methyl (II) and ortho-chloro (III) derivatives. Simultaneously, they revealed the minimum embryotoxic concentrations higher than that of aciclovir, what makes them safer than this pharmaceutic. Moreover, most of test compounds showed protective effects (better or comparable to that of ascorbic acid) on oxidatively-stressed erythrocytes. All the investigated compounds were effective at inhibiting the growth of human solid tumours of pharynx (FaDu) and tongue (SCC-25). The majority of molecules showed good selectivity indices. The most selective proved to be II showing in normal Vero cells over a 5-fold and an almost 3-fold decreased cytotoxicity relative to that in tumour SCC-25 and FaDu cells, respectively. Additionally, a 3,4-dichloro derivative (VI) was shown to possess concentration-dependent inhibitory effects on the replication of Herpes simplex virus type 1 and simultaneously at active concentrations was found to be nontoxic for normal Vero cells.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Compostos Aza/química , Citosina/análogos & derivados , Embrião não Mamífero/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Compostos Heterocíclicos de Anéis Fundidos/farmacologia , Peixe-Zebra , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Antivirais/química , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citosina/química , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Eritrócitos/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Compostos Heterocíclicos de Anéis Fundidos/química , Compostos Heterocíclicos de Anéis Fundidos/farmacocinética , Compostos Heterocíclicos de Anéis Fundidos/toxicidade , Células Vero , Replicação Viral/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento
19.
Bioorg Med Chem ; 27(6): 1023-1033, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738653

RESUMO

A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C6H4) displayed good inhibitory activity (HSV-1 EC50 1.5 µM, HSV-2 EC50 0.8 µM) and retained inhibitory activity in HSV-1 TK- cells (EC50 0.8 µM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds.


Assuntos
Aciclovir/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Aciclovir/síntese química , Aciclovir/química , Aciclovir/farmacologia , Antivirais/síntese química , Guanina/análogos & derivados , Guanina/síntese química , Guanina/farmacologia , Herpes Genital/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Humanos , Modelos Moleculares
20.
Eur J Med Chem ; 167: 546-561, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30798081

RESUMO

In recent years, new therapeutic possibilities were proposed for cardiac glycosides traditionally used to treat heart diseases, such as anticancer and antiviral activities. In this sense, this work aimed to synthesize the readily accessible 3ß-azido-3-deoxydigitoxigenin (5) from digitoxigenin (1). Two new series of compounds were obtained from derivative (5): (i) O-glycosyl trizols through click chemistry with propargyl glycosides; and (ii) compounds substituted in the alpha carbonyl position with different residues linked via an amino-group. All obtained derivatives have their chemical structures confirmed, and their anti-herpes (against HSV-types 1 and 2 replication) and cytotoxic (against PC3, A549, HCT-8 and LNCaP cell lines) activities evaluated. Compounds 10 and 11 exhibited the most promising results against HSV-1 (KOS and 29-R strains) and HSV-2 (333 strain) replication with SI values > 1000. Both compounds were also the most cytotoxic for the human cancer cell lines tested with IC50 values similar to those of paclitaxel. They also presented reduced toxicity toward non-cancerous cell lines (MRC-5 and HGF cells). Promising compounds were tested in regard to their ability to inhibit Na+/K+-ATPase. The inhibition rate correlates suitably with the bioactivity demonstrated by those both compounds against the different human cancer cells tested as well as against HSV replication. Moreover, the results showed that specific chemical features of compound 10 and 11 influenced the bioactivities tested. In summary, it was possible to obtain novel digitoxigenin-derivatives with remarkable cytotoxic and anti-herpes activities as well as low toxicity and high selectivity. In this way, they could be considered potential molecules for the development of new drugs.


Assuntos
Antineoplásicos/química , Antivirais/química , Digitoxigenina/farmacologia , Infecções por Herpesviridae/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Química Click , Digitoxigenina/análogos & derivados , Digitoxigenina/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos
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