RESUMO
cis-Aconitic acid is a constituent from the leaves of Echinodorus grandiflorus, a medicinal plant traditionally used in Brazil to treat inflammatory conditions, including arthritic diseases. The present study aimed to investigate the anti-arthritic effect of cis-aconitic acid in murine models of antigen-induced arthritis and monosodium urate-induced gout. The possible underlying mechanisms of action was evaluated in THP-1 macrophages. Oral treatment with cis-aconitic acid (10, 30, and 90 mg/kg) reduced leukocyte accumulation in the joint cavity and C-X-C motif chemokine ligand 1 and IL-1ß levels in periarticular tissue. cis-Aconitic acid treatment reduced joint inflammation in tissue sections of antigen-induced arthritis mice and these effects were associated with decreased mechanical hypernociception. Administration of cis-aconitic acid (30 mg/kg p.âo.) also reduced leukocyte accumulation in the joint cavity after the injection of monosodium urate crystals. cis-Aconitic acid reduced in vitro the release of TNF-α and phosphorylation of IκBα in lipopolysaccharide-stimulated THP-1 macrophages, suggesting that inhibition of nuclear factor kappa B activation was an underlying mechanism of cis-aconitic acid-induced anti-inflammatory effects. In conclusion, cis-aconitic acid has significant anti-inflammatory effects in antigen-induced arthritis and monosodium urate-induced arthritis in mice, suggesting its potential for the treatment of inflammatory diseases of the joint in humans. Additionally, our findings suggest that this compound may contribute to the anti-inflammatory effect previously reported for E. grandiflorus extracts.
Assuntos
Alismataceae , Gota , Humanos , Camundongos , Animais , Ácido Aconítico/farmacologia , Inibidor de NF-kappaB alfa , Ácido Úrico , Lipopolissacarídeos , NF-kappa B , Fator de Necrose Tumoral alfa , Ligantes , Alismataceae/química , Gota/induzido quimicamente , Gota/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quimiocinas , InflamaçãoRESUMO
There is growing interest in exploring Digitalis cardenolides as potential antiviral agents. Hence, we herein investigated the influence of structural features and lipophilicity on the antiherpes activity of 65 natural and semisynthetic cardenolides assayed inâ vitro against HSV-1. The presence of an α,ß-unsaturated lactone ring at C-17, a ß-hydroxy group at C-14 and C-3ß-OR substituents were considered essential requirements for this biological activity. Glycosides were more active than their genins, especially monoglycosides containing a rhamnose residue. The activity enhanced in derivatives bearing an aldehyde group at C-19 instead of a methyl group, whereas inserting a C-5ß-OH improved the antiherpes effect significantly. The cardenolides lipophilicity was accessed by measuring experimentally their log P values (n-octanol-water partition coefficient) and disclosed a range of lipophilicity (log P 0.75±0.25) associated with the optimal antiherpes activity. Inâ silico studies were carried out and resulted in the establishment of two predictive models potentially useful to identify and/or optimize novel antiherpes cardenolides. The effectiveness of the models was confirmed by retrospective analysis of the studied compounds. This is the first SAR study addressing the antiherpes activity of cardenolides. The developed computational models were able to predict the active cardenolides and their log P values.
Assuntos
Digitalis , Digitalis/química , Cardenolídeos/farmacologia , 1-Octanol , Ramnose , Estudos Retrospectivos , Extratos Vegetais/química , Antivirais/farmacologia , Glicosídeos , Lactonas , Aldeídos , ÁguaRESUMO
Cardiac glycosides (CGs) are useful drugs to treat cardiac illnesses and have potent cytotoxic and anticancer effects in cultured cells and animal models. Their receptor is the Na+,K+ ATPase, but other plasma membrane proteins might bind CGs as well. Herein, we evaluated the short- and long-lasting cytotoxic effects of the natural cardenolide glucoevatromonoside (GEV) on non-small-cell lung cancer H460 cells. We also tested GEV effects on Na+,K+ -ATPase activity and membrane currents, alone or in combination with selected chemotherapy drugs. GEV reduced viability, migration, and invasion of H460 cells spheroids. It also induced cell cycle arrest and death and reduced the clonogenic survival and cumulative population doubling. GEV inhibited Na+,K+-ATPase activity on A549 and H460 cells and purified pig kidney cells membrane. However, it showed no activity on the human red blood cell plasma membrane. Additionally, GEV triggered a Cl-mediated conductance on H460 cells without affecting the transient voltage-gated sodium current. The administration of GEV in combination with the chemotherapeutic drugs paclitaxel (PAC), cisplatin (CIS), irinotecan (IRI), and etoposide (ETO) showed synergistic antiproliferative effects, especially when combined with GEV + CIS and GEV + PAC. Taken together, our results demonstrate that GEV is a potential drug for cancer therapy because it reduces lung cancer H460 cell viability, migration, and invasion. Our results also reveal a link between the Na+,K+-ATPase and Cl- ion channels.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Cardenolídeos/farmacologia , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Citotoxinas/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologiaRESUMO
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 VeroRESUMO
Recent studies demonstrate that cardiac glycosides, known to inhibit Na+/K+-ATPase in humans, have increased susceptibility to cancer cells that can be used in tumor therapy. One of the most promising candidates identified so far is glucoevatromonoside, which can be isolated from the endangered species Digitalis mariana ssp. heywoodii. Due to its complex structure, glucoevatromonoside cannot be obtained economically by total chemical synthesis. Here we describe two methods for glucoevatromonoside production, both using evatromonoside obtained by chemical degradation of digitoxin as the precursor. 1) Catalyst-controlled, regioselective glycosylation of evatromonoside to glucoevatromonoside using 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as the sugar donor and 2-aminoethyldiphenylborinate as the catalyst resulted in an overall 30â% yield. 2) Biotransformation of evatromonoside using Digitalis lanata plant cell suspension cultures was less efficient and resulted only in overall 18â% pure product. Structural proof of products has been provided by extensive NMR data. Glucoevatromonoside and its non-natural 1-3 linked isomer neo-glucoevatromonoside obtained by semisynthesis were evaluated against renal cell carcinoma and prostate cancer cell lines.
Assuntos
Antineoplásicos/metabolismo , Cardenolídeos/metabolismo , Glicosídeos Cardíacos/metabolismo , Digitalis/metabolismo , Digitoxina/química , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Biotransformação , Cardenolídeos/síntese química , Cardenolídeos/isolamento & purificação , Cardenolídeos/farmacologia , Glicosídeos Cardíacos/síntese química , Glicosídeos Cardíacos/isolamento & purificação , Glicosídeos Cardíacos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Digitalis/química , Digitoxina/isolamento & purificação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Glicosilação , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Zika virus (ZIKV) is an arbovirus whose infection in humans can lead to severe outcomes. This article reviews studies reporting the anti-ZIKV activity of natural products (NPs) and derivatives published from 1997 to 2022, which were carried out with NPs obtained from plants (82.4%) or semisynthetic/synthetic derivatives, fungi (3.1%), bacteria (7.6%), animals (1.2%) and marine organisms (1.9%) along with miscellaneous compounds (3.8%). Classes of NPs reported to present anti-ZIKV activity include polyphenols, triterpenes, alkaloids, and steroids, among others. The highest values of the selectivity index, the ratio between cytotoxicity and antiviral activity (SI = CC50/EC50), were reported for epigallocatechin gallate (SI ≥ 25,000) and anisomycin (SI ≥ 11,900) obtained from Streptomyces bacteria, dolastane (SI = 1246) isolated from the marine seaweed Canistrocarpus cervicorni, and the flavonol myricetin (SI ≥ 862). NPs mostly act at the stages of viral adsorption and internalization in addition to presenting virucidal effect. The data demonstrate the potential of NPs for developing new anti-ZIKV agents and highlight the lack of studies addressing their molecular mechanisms of action and pre-clinical studies of efficacy and safety in animal models. To the best of our knowledge, none of the active compounds has been submitted to clinical studies.
Assuntos
Produtos Biológicos , Infecção por Zika virus , Zika virus , Humanos , Animais , Chlorocebus aethiops , Células Vero , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Replicação Viral , Antivirais/farmacologia , Antivirais/uso terapêuticoRESUMO
Leonotis nepetifolia (L.) Br. (Lamiaceae) is an African shrub popularly known as 'cordão-de-frade' in Brazil, traditionally used to treat infectious diseases, among other uses. This study aimed to investigate the phytochemical composition of hydroethanolic extracts from L. nepetifolia prepared from stems, leaves, roots and glomerulus, as well as their cytotoxicity, antileishmanial and antimicrobial activities. The chemical composition of the extracts was assessed by UPLC-ESI-MS/MS, whereas the antileishmanial activity was evaluated against promastigote and amastigote forms of Leishmania amazonensis. Cytotoxicity was tested on murine macrophages and the antimicrobial activity was investigated by a microdilution assay against several strains of fungi, Gram-positive and Gram-negative bacteria. The flavonoids apigenin, cirsiliol apigenin-7-O-glucoside, luteolin, luteolin-4'-O-glucoside, luteolin-4'-O- glucuronide and luteolin-7-O-glucoside were identified in all tested extracts. Extracts from leaves and roots showed more potent antileishmanial activity (IC50 32.90 µg mL-1 and 57.70 µg mL-1, respectively) against amastigotes forms in comparison to the other extracts. The leaf extract inhibited Bacillus cereus and Staphylococcus aureus growth (125 µg mL-1 and 100 µg mL-1, respectively), and also showed anti-Candida activity (10-125 µg mL-1). The biological effect can be related to the identified flavonoids. Our findings disclose the potential of L. nepetifolia as a source of bioactive compounds for the development of new therapeutic options for treating infectious diseases, especially flavonoids.
Assuntos
Anti-Infecciosos , Antiprotozoários/farmacologia , Lamiaceae , Extratos Vegetais/farmacologia , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antiprotozoários/isolamento & purificação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Lamiaceae/química , Leishmania/efeitos dos fármacos , Camundongos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Espectrometria de Massas em TandemRESUMO
Plants of the genus Digitalis produce 5 beta-cardenolides that are used in the therapy of cardiac insufficiency in humans. 3 beta-Hydroxysteroid dehydrogenase (3 beta-HSD) and progesterone 5 beta-reductase (P5 betaR) are both supposed to be important enzymes in the biosynthesis of these natural products. Activity and gene expression were demonstrated for both enzymes in cardenolide-accumulating leaves of Digitalis lanata but also in cardenolide-free permanent cell suspension cultures initiated from D. lanata leaf tissue. Enzyme activities were determined and quantified by HPLC and GC-MS methods. Expression of the respective genes, namely AY585867.1 (P5betaR gene) and DQ466890.1 (3beta-HSD gene), was made evident by real-time polymerase chain reaction (qPCR) analysis. We demonstrate for the first time that the P5betaR gene, encoding an enzyme described as a key enzyme in cardenolide biosynthesis, is also expressed in cardenolide-free tissues of cardenolide-containing plants.
Assuntos
3-Hidroxiesteroide Desidrogenases/metabolismo , Cardenolídeos/metabolismo , Digitalis/genética , Expressão Gênica , Genes de Plantas , Oxirredutases/metabolismo , 3-Hidroxiesteroide Desidrogenases/genética , Técnicas de Cultura de Células , Digitalis/enzimologia , Digitalis/metabolismo , Oxirredutases/genética , Folhas de Planta , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Infection by nematodes is a problem for human health, livestock, and agriculture, as it causes deficits in host health, increases production costs, and incurs a reduced food supply. The control of these parasites is usually done using anthelmintics, which, in most cases, have not been fully effective. Therefore, the search for new molecules with anthelmintic potential is necessary. METHODS: In the present study, we isolated and characterized molecules from the nematophagous fungus Pochonia chlamydosporia and tested these compounds on three nematodes: Caenorhabditis elegans; Ancylostoma ceylanicum; and Ascaris suum. RESULTS: The ethyl acetate extract showed nematicidal activity on the nematode model C. elegans. We identified the major substance present in two sub-fractions of this extract as ketamine. Then, we tested this compound on C. elegans and the parasites A. ceylanicum and A. suum using hamsters and mice as hosts, respectively. We did not find a difference between the animal groups when considering the number of worms recovered from the intestines of animals treated with ketamine (6 mg) and albendazole (P > 0.05). The parasite burden of larvae recovered from the lungs of mice treated with ketamine was similar to those treated with ivermectin. CONCLUSIONS: The results presented here demonstrate the nematicidal activity of ketamine in vitro and in vivo, thus confirming the nematicidal potential of the molecule present in the fungus P. chlamydosporia may consist of a new method of controlling parasites.
Assuntos
Hypocreales/metabolismo , Ketamina , Nematoides , Albendazol/farmacologia , Ancylostoma/efeitos dos fármacos , Animais , Antinematódeos/metabolismo , Antinematódeos/farmacologia , Ascaris suum/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Cricetinae , Ivermectina/farmacologia , Ketamina/metabolismo , Ketamina/farmacologia , Camundongos , Nematoides/efeitos dos fármacos , Nematoides/microbiologia , Controle Biológico de Vetores/métodosRESUMO
The antihypertensive activity of the medicinal plant Hancornia speciosa has been previously demonstrated by us, being the activity ascribed to polyphenols and cyclitols like l-(+)-bornesitol. We herein evaluated the stability of the bioactive marker bornesitol submitted to forced degradation conditions. Bornesitol employed in the study was isolated from H. speciosa leaves. An UHPLC-ESI-MS/MS method was developed to investigate bornesitol stability based on MRM (Multiple Reaction Monitoring) acquisition mode and negative ionization mode, employing both specific (m/z 193â¯ââ¯161â¯Da) and confirmatory (m/z 193â¯ââ¯175â¯Da) transitions. A gradient elution of 0.1% formic acid in water and acetonitrile was performed on a HILIC column. The method was validated and showed adequate linearity (r2â¯>â¯0.99), selectivity, specificity, accuracy, and precision (RSDâ¯<â¯2.9%). The method was robust for deliberate variations on dessolvation temperature, but not for changes in the flow rate and dessolvation gas. The results from the stability studies allowed us to classify bornesitol as labile for acidic and alkaline hydrolysis, but as very stable for oxidative and neutral hydrolysis exposure. Bornesitol was categorized as practically stable under photolysis degradation, whereas a considerable reduction on its contents was induced by metal ions and thermolysis exposure. Degraded samples from neutral hydrolysis and thermolysis were assayed in vitro for ACE inhibition and showed a substantial decrease in biological activity as compared to intact bornesitol. myo-Inositol was identified as the major degradation products in both matrices. This is the first report on bornesitol stability under different stress conditions and the obtained data are relevant for the development and quality control of standardized products from H. speciosa leaves.
Assuntos
Apocynaceae/química , Cromatografia Líquida de Alta Pressão/métodos , Ciclitóis , Espectrometria de Massas/métodos , Peptidil Dipeptidase A/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Biomarcadores/análise , Biomarcadores/química , Ciclitóis/análise , Ciclitóis/química , Ciclitóis/farmacologia , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/química , Reprodutibilidade dos TestesRESUMO
Cardiac glycosides (CGs) are natural compounds used to treat congestive heart failure. They have garnered attention as a potential cancer treatment option, especially because they bind to Na+/K+-ATPase as a target and activate intracellular signaling pathways leading to a variety of cellular responses. In this study we evaluated AMANTADIG, a semisynthetic cardenolide derivative, for its cytotoxic activity in two human androgen-insensitive prostate carcinoma cell lines, and the potential synergistic effects with docetaxel. AMANTADIG induced cytotoxic effects in both cell lines, and a combination with docetaxel showed a moderate and strong synergism in DU145 and PC-3 cells, respectively, at concentrations considerably lower than their IC50 values. Cell cycle analyses showed that AMANTADIG and its synergistic combination induced G2/M arrest of DU145 and PC-3 cells by modulating Cyclin B1, CDK1, p21 and, mainly, survivin expression, a promising target in cancer therapy. Furthermore, AMANTADIG presented reduced toxicity toward non-cancerous cell type (PBMC), and computational docking studies disclosed high-affinity binding to the Na+/K+-ATPase α subunit, a result that was experimentally confirmed by Na+/K+-ATPase inhibition assays. Hence, AMANTADIG inhibited Na+/K+-ATPase activity in PC-3 cells, as well as in purified pig kidney at nanomolar range. Altogether, these data highlight the potent effects of AMANTADIG in combination with docetaxel and offer important insights for the development of more effective and selective therapies against prostate cancer.
Assuntos
Apoptose/efeitos dos fármacos , Digitoxigenina/análogos & derivados , Docetaxel/farmacologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Digitoxigenina/química , Digitoxigenina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Simulação de Acoplamento Molecular , Necrose , Neoplasias da Próstata/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Survivina/genética , Survivina/metabolismoRESUMO
Malaria is the most common parasitic disease in humans. It is estimated that 3 billion people live under the risk of contracting this disease in the world. Chloroquine (CQ) is the drug of choice to treat cases of non-complicated malaria. Forced degradation studies are important to know the drug's potentials degradation products and to develop a stability indicating method. Thus, chloroquine active pharmaceutical ingredient (API), chloroquine tablets and placebo were submitted to a detailed forced degradation study, using several stressing agents. The results were used on the development of a stability indicating method, using high performance liquid chromatography. The method was validated showing selectivity, precision, accuracy, robustness and linearity in the range of 30-360µg/mL of chloroquine. Chloroquine API and tablets were susceptible to alkaline hydrolysis with NaOH 1mol/L, and to oxidation with H2O2 3.0%. Two degradation products were formed in oxidative test. Kinetics of chloroquine degradation in alkaline hydrolysis was performed for both API and tablets. The calculated decay constant (k1) was 0.223days-1 for API and 0.182days-1 for tablets, while the half-life (t1/2) was 3.1days for API and 3.8days for tablets. Chemical structures have been proposed for the two degradation products formed in the presence of H2O2, using an UHPLC-UV-MS/MS approach.
Assuntos
Cromatografia Líquida de Alta Pressão , Cloroquina , Estabilidade de Medicamentos , Peróxido de Hidrogênio , Oxirredução , Reprodutibilidade dos Testes , Comprimidos , Espectrometria de Massas em TandemRESUMO
The development of new and cost-effective alternative therapeutic strategies to treat leishmaniasis has become a high priority. In the present study, the antileishmanial activity of Strychnos pseudoquina St. Hil. was investigated and pure compounds that presented this biological effect were isolated. An ethyl acetate extract was prepared, and it proved to be effective against Leishmania amazonensis. A bioactivity-guided fractionation was performed, and two flavonoids were identified, quercetin 3-O-methyl ether and strychnobiflavone, which presented an effective antileishmanial activity against L. amazonensis, and studies were extended to establish their minimum inhibitory concentrations (IC50), their leishmanicidal effects on the intra-macrophage Leishmania stage, as well as their cytotoxic effects on murine macrophages (CC50), and in O+ human red blood cells. The data presented in this study showed the potential of an ethyl acetate extract of S. pseudoquina, as well as two flavonoids purified from it, which can be used as a therapeutic alternative on its own, or in association with other drugs, to treat disease evoked by L. amazonensis.
RESUMO
Cell cultures of Digitalis species are known to accept exogenous substrates for biotransformation reactions. We here report the biotransformation of 21-O-acetyl-deoxycorticosterone (1) by cell suspension cultures of Digitalis lanata strain W.1.4. Nine derivatives of 1 were obtained and their chemical structures determined by spectroscopic methods. 2ß-Hydroxylation and C-21-glucosylation of the steroidal nucleus were described for the first time in suspension-cultured plant cells. Steroid 5α- and 5ß-reduction products were also observed. Among the compounds isolated and structures elucidated were 2ß,3ß,21-trihydroxy-4-pregnen-20-one, 2ß,3α,21-trihydroxy-4-pregnen-20-one and 3ß,21-dihydroxy-5α-pregnan-20-one-3ß-O-ß-glucoside.
Assuntos
Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/metabolismo , Digitalis/citologia , Digitalis/metabolismo , Absorção , Biotransformação , Células Cultivadas , Desoxicorticosterona/análise , Desoxicorticosterona/química , SuspensõesRESUMO
Cardiac glycosides, known ligands of the sodium pump, are widely used in the treatment of heart failure, such as digoxin and digitoxin. Besides this important activity, other biological activities, such as the antiviral activity, have been described for this group. HSV are responsible for many infections of oral, ocular and genital regions. Treatment with nucleoside analogs such as acyclovir is effective in most cases; however drug-resistance may arise due to prolonged treatment mainly in immunocompromised individuals. In this study, an antiherpes screening was performed with 65 cardenolide derivatives obtained from different sources, and one natural cardenolide, glucoevatromonoside, inhibited HSV-1 and HSV-2 replication at very low concentrations. This cardenolide showed viral inhibitory effects if added up to 12h p.i. and these effects appear to take place by the inhibition of viral proteins synthesis (ICP27, U(L)42, gB, gD), the blockage of virus release and the reduction of viral cell-to-cell spread. This compound also showed synergistic antiviral effects with acyclovir and anti-Na(+)K(+)ATPase activity, suggesting that cellular electrochemical gradient alterations might be involved in the mechanism of viral inhibition. These results suggest that cardenolides might be promising for future antiviral drug design.