RESUMO
Respiratory syncytial virus (RSV) stands as the foremost cause of infant hospitalization globally, ranking second only to malaria in terms of infant mortality. Although three vaccines have recently been approved for the prophylaxis of adults aged 60 and above, and pregnant women, there is currently no effective antiviral drug for treating RSV infections. The only preventive measure for infants at high risk of severe RSV disease is passive immunization through monoclonal antibodies. This Perspective offers an overview of the latest advancements in RSV drug discovery of small molecule antivirals, with particular focus on the promising findings from agents targeting the fusion and polymerase proteins. A comprehensive reflection on the current state of RSV research is also given, drawing inspiration from the lessons gleaned from HCV and HIV, while also considering the impact of the recent approval of the three vaccines.
Assuntos
Antivirais , Descoberta de Drogas , Infecções por Vírus Respiratório Sincicial , Antivirais/farmacologia , Antivirais/química , Antivirais/uso terapêutico , Humanos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacosRESUMO
Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5'-methyl [(S)-hydroxy(phenoxy)phosphoryl]-l-alaninate in combination with 2',3'-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo- and picornaviruses.
Assuntos
Antivirais , Picornaviridae , Pró-Fármacos , Infecções por Vírus Respiratório Sincicial , Animais , Antivirais/farmacologia , Antivirais/química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Chlorocebus aethiops , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Humanos , Picornaviridae/efeitos dos fármacos , Relação Estrutura-Atividade , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Descoberta de Drogas , Nucleosídeos/química , Nucleosídeos/farmacologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/virologiaRESUMO
AIMS: The study evaluated the antiviral effect of Verapamil against respiratory syncytial virus (RSV) and investigated its underlying mechanism. MATERIALS AND METHODS: RSV-infected BALB/c mice were treated with Verapamil. Body weight, survival rates, viral load, lung damage, inflammatory factors, and the expression of RSV fusion (F) protein were analyzed. In cellular studies, intracellular Ca2+ and viral titers were measured in the presence of Verapamil, Calcium Chloride, and EGTA. A time-of-addition assay assessed the antiviral effect of Verapamil. KEY FINDINGS: Mice infected with RSV and treated with Verapamil exhibited a significant decrease in weight loss, an increase in survival rates, and reductions in viral titers, RSV F protein expression, inflammatory responses, and lung tissue injury. Verapamil reduced intracellular calcium levels, which correlated with reduced viral titers. The addition of calcium chloride reversed the anti-viral effects mediated by Verapamil, while EGTA potentiated them. The antiviral activity of Verapamil was observed during the early phase of RSV infection, likely by blocking Ca2+ channels and inhibiting virus replication. SIGNIFICANCE: Verapamil effectively inhibits RSV infection by blocking calcium channels and reducing intracellular calcium levels, thereby impeding viral replication. Thus, Verapamil shows promise as a treatment for RSV.
Assuntos
Antivirais , Cálcio , Camundongos Endogâmicos BALB C , Infecções por Vírus Respiratório Sincicial , Verapamil , Verapamil/farmacologia , Animais , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Cálcio/metabolismo , Camundongos , Antivirais/farmacologia , Feminino , Replicação Viral/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Humanos , Carga Viral/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Pulmão/virologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacosRESUMO
Ten C-geranylated flavonoids, along with three known analogues, were isolated from the leaves of Artocarpus communis. The chemical structures of these compounds were unambiguously determined via comprehensive spectroscopic analysis, single-crystal X-ray diffraction experiments, and quantum chemical electronic circular dichroism calculations. Structurally, artocarones A-I (1-9) represent a group of unusual, highly modified C-geranylated flavonoids, in which the geranyl chain is cyclised with the ortho-hydroxy group of flavonoids to form various heterocyclic scaffolds. Notably, artocarones E and G-I (5 and 7-9) feature a 6H-benzo[c]chromene core that is hitherto undescribed in C-geranylated flavonoids. Artocarone J (10) is the first example of C-9-C-16 connected C-geranylated aurone. Meanwhile, the plausible biosynthetic pathways for these rare C-geranylated flavonoids were also proposed. Notably, compounds 1, 2, 4, 8, 11, and 12 exhibited promising in vitro inhibitory activities against respiratory syncytial virus and herpes simplex virus type 1.
Assuntos
Antivirais , Artocarpus , Flavonoides , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Artocarpus/química , Antivirais/química , Antivirais/farmacologia , Antivirais/isolamento & purificação , Estrutura Molecular , Herpesvirus Humano 1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Folhas de Planta/química , Relação Estrutura-Atividade , Modelos MolecularesRESUMO
BACKGROUND: Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive. PURPOSE: This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection. METHODS: BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism. RESULTS: Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes. CONCLUSION: Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Macrófagos Alveolares , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR , Quercetina , Infecções por Vírus Respiratório Sincicial , Succinatos , Animais , Succinatos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Quercetina/farmacologia , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Succinato Desidrogenase/metabolismo , Glicólise/efeitos dos fármacos , Feminino , Transdução de Sinais/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , HidroliasesRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: WuHuTang (WHT) is a traditional Chinese medicine compound for treating asthma, and the evidence supports that it has a good effect on acute asthma attacks in children and adults. Respiratory syncytial virus (RSV) is an important factor in the pathogenesis of acute asthma attacks, and the effect on dendritic cells is the key to its pathogenesis. Previous studies have confirmed that the pathogenesis of viruses is related to exosomes. However, there are few studies on the exosomes induced by RSV. Whether WHT can improve the changes caused by RSV-induced exosomes or not is worthy of further exploration. AIM OF THE STUDY: We aim to study the effects of RSV-induced exosomes on the function and autophagy of dendritic cells, and to observe the intervention effect of WHT serum on the above effects. METHODS: The co-culture model of exosomes derived from bone marrow mesenchymal stem cells induced by RSV (BMSCs-Exo-RSV) and dendritic cells was established, and then WHT serum was used to intervene. After 24 h of intervention, the CCK-8 method, flow cytometry, Elisa, RT-qCPR, and Western blot were used to detect the above-mentioned culture model. RESULTS: RSV-induced exosomes had certain effects on viability, apoptosis, and costimulatory molecules generation of dendritic cells. At the same time, the levels of IL-6, IL-12, TNF-α, and autophagy increased, while the levels of IL-4, IL-10, and TGF-ß decreased, and the AKT/TSC/mTOR pathway was inhibited. WHT serum could activate this pathway and reverse the above changes in dendritic cells. CONCLUSION: This study reveals that the pathogenic effect of RSV is related to the exosomes induced by RSV. The exosomes induced by RSV affect the function of dendritic cells by inhibiting the AKT/TSC/mTOR pathway, which can be activated by WHT to reverse the effects caused by RSV-induced exosomes.
Assuntos
Autofagia , Células Dendríticas , Medicamentos de Ervas Chinesas , Exossomos , Serina-Treonina Quinases TOR , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Exossomos/metabolismo , Exossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Animais , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Técnicas de Cocultura , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/fisiologia , Células Cultivadas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Citocinas/metabolismo , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacosRESUMO
Seaweed polysaccharides, particularly sulfated ones, exhibited potent antiviral activity against a wide variety of enveloped viruses, such as herpes simplex virus and respiratory viruses. Different mechanisms of action were suggested, which may range from preventing infection to intracellular antiviral activity, at different stages of the viral cycle. Herein, we generated two chemically engineered sulfated fucans (C303 and C304) from Cystoseira indica by an amalgamated extraction-sulfation procedure using chlorosulfonic acid-pyridine/N,N-dimethylformamide and sulfur trioxide-pyridine/N,N-dimethylformamide reagents, respectively. These compounds exhibited activity against HSV-1 and RSV with 50 % inhibitory concentration values in the range of 0.75-2.5 µg/mL and low cytotoxicity at concentrations up to 500 µg/mL. The antiviral activities of chemically sulfated fucans (C303 and C304) were higher than the water (C301) and CaCl2 extracted (C302) polysaccharides. Compound C303 had a (1,3)-linked fucan backbone and was branched. Sulfates were present at positions C-2, C-4, and C-2,4 of Fucp, and C-6 of Galp residues of this polymer. Compound C304 had a comparable structure but with more sulfates at C-4 of Fucp residue. Both C303 and C304 were potent antiviral candidates, acting in a dose-dependent manner on the adsorption and other intracellular stages of HSV-1 and RSV replication, in vitro.
Assuntos
Antivirais , Herpesvirus Humano 1 , Polissacarídeos , Antivirais/farmacologia , Antivirais/química , Chlorocebus aethiops , Herpesvirus Humano 1/efeitos dos fármacos , Polissacarídeos/farmacologia , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Animais , Células Vero , Humanos , Sulfatos/química , Sulfatos/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacosRESUMO
A phytochemical investigation on the buds of edible medicinal plant, Eugenia carvophyllata, led to the discovery of seven new compounds, caryophones A-G (1-7), along with two biogenetically-related known ones, 2-methoxy-7-methyl-1,4-naphthalenedione (8) and eugenol (9). Compounds 1-3 represent the first examples of C-5-C-1' connected naphthoquinone-monoterpene adducts with a new carbon skeleton. Compounds 4-7 are a class of novel neolignans with unusual linkage patterns, in which the C-9 position of one phenylpropene unit coupled with the aromatic core of another phenylpropene unit. The chemical structures of the new compounds were determined based on extensive spectroscopic analysis, X-ray diffraction crystallography, and quantum-chemical calculation. Among the isolates, compounds (-)-2, 3, 6, and 9 showed significant in vitro inhibitory activities against respiratory syncytial virus (RSV)-induced nitric oxide (NO) production in RAW264.7 cells.
Assuntos
Anti-Inflamatórios , Eugenia , Lignanas , Naftoquinonas , Óxido Nítrico , Compostos Fitoquímicos , Camundongos , Células RAW 264.7 , Animais , Óxido Nítrico/metabolismo , Estrutura Molecular , Lignanas/farmacologia , Lignanas/isolamento & purificação , Lignanas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Naftoquinonas/farmacologia , Naftoquinonas/isolamento & purificação , Naftoquinonas/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Eugenia/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , ChinaRESUMO
Respiratory syncytial virus (RSV) infects neuronal cells in the central nervous system (CNS), resulting in neurological symptoms. In the present study, we intended to explore the mechanism of RSV infection-induced neuroinflammatory injury from the perspective of the immune response and sought to identify effective protective measures against the injury. The findings showed that toll-like receptor 4 (TLR4) was activated after RSV infection in human neuronal SY5Y cells. Furthermore, TLR4 activation induced autophagy and apoptosis in neuronal cells, promoted the formation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and increased the secretion of downstream inflammatory cytokines such as interleukin-1ß (IL-1ß), interleukin-18 (IL-18) and tumour necrosis factor-α (TNF-α). Interestingly, blockade of TLR4 or treatment with exogenous melatonin significantly suppressed TLR4 activation as well as TLR4-mediated apoptosis, autophagy and immune responses. Therefore, we infer that melatonin may act on the TLR4 to ameliorate RSV-induced neuronal injury, which provides a new therapeutic target for RSV infection.
Assuntos
Apoptose , Autofagia , Inflamassomos , Melatonina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Infecções por Vírus Respiratório Sincicial , Receptor 4 Toll-Like , Humanos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sistema Nervoso Central/virologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Citocinas/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Melatonina/farmacologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/fisiologia , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismoRESUMO
Three new (1-3) and six known rotenoids (5-10), along with three known isoflavones (11-13), were isolated from the leaves of Millettia oblata ssp. teitensis. A new glycosylated isoflavone (4), four known isoflavones (14-18), and one known chalcone (19) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC50 values of 0.7 and 3.4 µg/mL, respectively. Compounds 6, 8, 10, 11, and 14 showed anti-RSV activity with IC50 values of 0.4-10 µM, while compound 3 exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC50 of 4.2 µM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds 3, 11, and 14 exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.
Assuntos
Antivirais , Isoflavonas , Millettia , Isoflavonas/farmacologia , Isoflavonas/química , Isoflavonas/isolamento & purificação , Antivirais/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Millettia/química , Estrutura Molecular , Humanos , Rotenona/farmacologia , Rotenona/química , Rotenona/análogos & derivados , Folhas de Planta/química , Raízes de Plantas/química , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacosRESUMO
Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 µM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.
Assuntos
Polienos , Polienos/química , Polienos/farmacologia , Estrutura Molecular , Talaromyces/química , Antivirais/farmacologia , Antivirais/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , HumanosRESUMO
BACKGROUND: Respiratory viruses have been reported to infect the salivary glands and the throat, which are potential reservoirs for virus replication and transmission. Therefore, strategies to reduce the amount of infective virus particles in the oral mucous membranes could lower the risk of transmission. METHODS: The viral inactivation capacity of a plant-oil-based oral rinse (Salviathymol®) was evaluated in comparison with chlorhexidine (Chlorhexamed® FORTE) using a quantitative suspension test according to EN 14476. FINDINGS: Salviathymol efficiently inactivated severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), respiratory syncytial virus (RSV) and two influenza strains to undetectable levels. CONCLUSION: Salviathymol has potential as preventive measure to lower transmission of respiratory viruses.
Assuntos
Antissépticos Bucais , SARS-CoV-2 , Humanos , Antissépticos Bucais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Óleos de Plantas/farmacologia , Antivirais/farmacologia , Inativação de Vírus/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , COVID-19/prevenção & controleRESUMO
A 1H-isoindol-3-amine was identified as suitable P1 group for the proprotein convertase furin using a crystallographic screening with a set of 20 fragments known to occupy the S1 pocket of trypsin-like serine proteases. Its binding mode is very similar to that observed for the P1 group of benzamidine-derived peptidic furin inhibitors suggesting an aminomethyl substitution of this fragment to obtain a couplable P1 residue for the synthesis of substrate-analogue furin inhibitors. The obtained inhibitors possess a slightly improved picomolar inhibitory potency compared to their benzamidine-derived analogues. The crystal structures of two inhibitors in complex with furin revealed that the new P1 group is perfectly suited for incorporation in peptidic furin inhibitors. Selected inhibitors were tested for antiviral activity against respiratory syncytial virus (RSV) and a furin-dependent influenza A virus (SC35M/H7N7) in A549 human lung cells and demonstrated an efficient inhibition of virus activation and replication at low micromolar or even submicromolar concentrations. First results suggest that the Mas-related G-protein coupled receptor GPCR-X2 could be a potential off-target for certain benzamidine-derived furin inhibitors.
Assuntos
Antivirais , Desenho de Fármacos , Furina , Furina/antagonistas & inibidores , Furina/metabolismo , Humanos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Estrutura-Atividade , Células A549 , Vírus da Influenza A/efeitos dos fármacos , Cristalografia por Raios X , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Estrutura Molecular , Modelos Moleculares , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Relação Dose-Resposta a DrogaRESUMO
Forsyqinlingines C (1) and D (2), two C9 -monoterpenoid alkaloids bearing a rare skeleton, were isolated from the ripe fruits of Forsythia suspensa. Their structures, including absolute configurations, were fully elucidated by extensive spectroscopic data and ECD experiments. The plausible biogenetic pathway for compounds 1 and 2 was also proposed. In vitro, two C9 -monoterpenoid alkaloids showed anti-inflammatory activity performed by the inhibitory effect on the release of ß-glucuronidase in rat polymorphonuclear leukocytes (PMNs), as well as antiviral activity against influenza A (H1N1) virus and respiratory syncytial virus (RSV).
Assuntos
Alcaloides/química , Anti-Inflamatórios/química , Antivirais/química , Forsythia/química , Monoterpenos/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antivirais/isolamento & purificação , Antivirais/farmacologia , Forsythia/metabolismo , Frutas/química , Frutas/metabolismo , Glucuronidase/metabolismo , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fator de Ativação de Plaquetas/farmacologia , Ratos , Vírus Sinciciais Respiratórios/efeitos dos fármacosRESUMO
L-sulforaphane (LSF) is an isothiocyanate derived from cruciferous vegetables that has long been known for its anticarcinogenic, antioxidant and anti-inflammatory effects. LSF also possesses antimicrobial properties, although the evidence for this is limited. Respiratory pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes and respiratory syncytial virus (RSV), are leading global causes of illness and death among children aged under five years, particularly in resource-poor countries where access to vaccines are limited or, in the case of S. pyogenes and RSV, vaccines have not been licensed for use in humans. Therefore, alternative strategies to prevent and/or treat these common infectious diseases are urgently needed. This study was conducted to investigate the antimicrobial effects of LSF against common respiratory pathogens, S. pneumoniae (serotypes 1 and 6B), H. influenzae type B (HiB), non-typeable H. influenzae (NTHi), S. pyogenes and RSV in relevant human cell-based models. LSF significantly inhibited the growth of H. influenzae, but not S. pneumoniae or S. pyogenes. LSF did not improve opsonophagocytic capacity or killing by human phagocytic cell lines (HL-60s and THP-1 macrophages) for S. pneumoniae yet showed some improved killing for H. influenzae species in THP-1 macrophages. However, LSF significantly reduced RSV infection in human lung epithelial cells, associated with increased expression of cyclin D1 (CCND1) gene as well as the antioxidant genes, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HMOX-1). Overall, LSF represents an exciting avenue for further antimicrobial research, particularly as a novel therapy against H. influenzae species and RSV.
Assuntos
Antibacterianos/farmacologia , Infecções por Haemophilus/tratamento farmacológico , Isotiocianatos/farmacologia , Infecções Pneumocócicas/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Sulfóxidos/farmacologia , Linhagem Celular , Ciclina D1/metabolismo , Células HL-60 , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/crescimento & desenvolvimento , Heme Oxigenase-1/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Testes de Sensibilidade Microbiana , Fator 2 Relacionado a NF-E2/metabolismo , Opsonização/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Infecções Respiratórias/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/crescimento & desenvolvimento , Células THP-1 , Verduras/químicaRESUMO
OBJECTIVE: Exploration of the underlying molecular mechanism of Jinchan Oral Liquid (JOL) in treating children with the respiratory syncytial virus (RSV) pneumonia to provide new evidence for the clinical application. METHODS: The active components and target genes of JOL were screened by the TCMSP database. The targets of RSV pneumonia were obtained from the GeneCards, OMIM, DrugBank, and PharmGKB database. Then, we constructed the active component-target network and screened the core genes. The overlaps were screened for PPI network analysis, GO analysis, and KEGG analysis. Finally, result validation was performed by molecular docking. RESULTS: According to the screening criteria of the ADME, 74 active compounds of JOL were obtained; after removing redundant targets, we selected 180 potential targets. By screening the online database, 893 RSV pneumonia-related targets were obtained. A total of 82 overlapping genes were chosen by looking for the intersection. The STRING online database was used to acquire PPI relationships, and 16 core genes were obtained. GO and KEGG analyses showed that the main pathways of JOL in treating RSV pneumonia include TNF signaling pathway and IL17 signaling pathway. The molecular docking results showed that the active compounds of JOL had a good affinity with the core genes. CONCLUSION: In this study, we preliminarily discussed the main active ingredients, related targets, and pathways of JOL and predicted the pharmacodynamic basis and the potential therapeutic mechanisms of RSV pneumonia. In summary, the network pharmacology strategy may be helpful for the discovery of multitarget drugs against complex diseases.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Redes Reguladoras de Genes/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Criança , Biologia Computacional/métodos , Bases de Dados Genéticas , Desenvolvimento de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Humanos , Simulação de Acoplamento Molecular , Mapas de Interação de Proteínas , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Transdução de SinaisRESUMO
Influenza and RSV are human viruses responsible for outbreaks in hospitals, long-term care facilities and nursing homes. The present study assessed an air treatment using ozone at two relative humidity conditions (RHs) in order to reduce the infectivity of airborne influenza. Bovine pulmonary surfactant (BPS) and synthetic tracheal mucus (STM) were used as aerosols protectants to better reflect the human aerosol composition. Residual ozone concentration inside the aerosol chamber was also measured. RSV's sensitivity resulted in testing its resistance to aerosolization and sampling processes instead of ozone exposure. The results showed that without supplement and with STM, a reduction in influenza A infectivity of four orders of magnitude was obtained with an exposure to 1.70 ± 0.19 ppm of ozone at 76% RH for 80 min. Consequently, ozone could be considered as a virucidal disinfectant for airborne influenza A. RSV did not withstand the aerosolization and sampling processes required for the use of the experimental setup. Therefore, ozone exposure could not be performed for this virus. Nonetheless, this study provides great insight for the efficacy of ozone as an air treatment for the control of nosocomial influenza A outbreaks.
Assuntos
Vírus da Influenza A/efeitos dos fármacos , Ozônio/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Inativação de Vírus/efeitos dos fármacos , Aerossóis , Microbiologia do Ar , Infecção Hospitalar/prevenção & controle , Desinfecção/métodos , Humanos , Influenza Humana/prevenção & controle , Ozônio/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Vírus Respiratório Sincicial/prevenção & controleRESUMO
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children, and specific treatment for RSV infections remains unavailable. We herein reported a series of substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent RSV inhibitors. Among them, six low cytotoxic compounds (11, 12, 15, 22, 26, and 28) have been identified and selected to study associated inhibitory mechanisms. All these compounds suppressed not only the viral replication but also RSV-induced IRF3 and NF-κB activation and associated production of cytokines/chemokines. The two most potent compounds (15 and 22) were selected for further molecular mechanism studies associated with their suppression effect on RSV-activated IRF3 and NF-κB. These two compounds decreased RSV-induced IRF3 phosphorylation at serine 396 and p65 phosphorylation at serine 536 at both early and late infection phases. In addition, compound 22 also inhibited RSV-induced p65 phosphorylation at serine 276 at the late phase of RSV infection.
Assuntos
Antivirais/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Inflamação/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Células A549 , Benzamidas/uso terapêutico , Humanos , Inflamação/etiologia , Infecções por Vírus Respiratório Sincicial/complicações , Vírus Sinciciais Respiratórios/fisiologiaRESUMO
The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.
Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Predisposição Genética para Doença , Influenza Humana/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/uso terapêutico , Variação Biológica Individual , COVID-19/genética , COVID-19/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/virologia , Expressão Gênica , Humanos , Imunidade Inata , Fatores Imunológicos/uso terapêutico , Influenza Humana/tratamento farmacológico , Influenza Humana/genética , Influenza Humana/virologia , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/imunologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/imunologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Tratamento Farmacológico da COVID-19RESUMO
We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a, identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target compounds 1b, 1g-h, 1af and 1ah (IC50 = 3.10-6.93 µM) had good in vitro activity against RSV, which were better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity (CC50: 2490.33 µM) and the highest selective index (SI = 673.06), suggesting its promising potential as a candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai (IC50s: 1.87-14.28 µM) were more active against IAV than or comparable to ribavirin (IC50: 15.36 ± 0.93 µM). Particularly, the most active compound 1ae (IC50: 1.87 ± 0.58 µM) was found to be 8.2-fold more potent than the reference drug, which could inhibit the virus transcription and replication cycle at an early stage.