RESUMO
Zanthoxylum acanthopodium DC. is a widely used traditional medicinal plant to treat fever, flu, stomachache, traumatic injury, and mosquito bite in tropical and subtropical Asia. This study aimed to investigate the antifungal, anti-inflammatory, antiviral, and larvicidal activities of its fruit essential oil. The essential oil sample from China (EOZC) was mainly composed of limonene (29.78%) and ß-myrcene (26.65%), while the sample from Myanmar (EOZM) was dominated by Terpinen-4-ol (43.35%). Both essential oils showed antifungal activity, with 90% minimum inhibitory concentration (MIC90) values ranging from 26.3 to 499 µg/mL. By obviously inhibiting nitric oxide (NO) in RAW 264.7 cells, EOZC (IC50, 16 µg/mL) showed comparable anti-inflammatory activity to the positive control L-NMMA (IC50, 12.2 µg/mL). EOZM showed significant antiviral activity against the dengue virus with an IC50 value of 13 µg/mL. Additionally, both EOZC and EOZM demonstrated dose-dependent larvicidal activity against Aedes albopictus, with LC50 and LC90 values ranging from 45.8 to 144.0 µg/mL. Our results contribute a theoretical foundation for the further application of Zanthoxylum acanthopodium DC. as an antifungal and anti-inflammatory ingredient in the pharmaceutical industry and further indicate that it has the potential to be developed as a new source of natural and eco-friendly medicine for the prevention and treatment of dengue virus.
Assuntos
Aedes , Inseticidas , Óleos Voláteis , Zanthoxylum , Animais , Anti-Inflamatórios/farmacologia , Antifúngicos/farmacologia , Antivirais/farmacologia , Inseticidas/farmacologia , Larva , Mianmar , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Zanthoxylum/químicaRESUMO
Hierarchical virtual screening combined with ADME prediction and cluster analysis methods were used to identify influenza virus PB2 inhibitors with high activity, good druggability properties, and diverse structures. The 200,000 molecules in the ChemDiv core library were narrowed down to a final set of 97 molecules, of which six compounds were found to rescue cells from both H1N1 and H3N2 virus-induced CPE with EC50 values ranging from 5.81 µM to 42.77 µM, and could bind to the PB2 CBD of H1N1, with Kd values of 0.11 µM to 6.4 µM. The six compounds have novel structures and low molecular weight and are, thus, suitable serve as lead compounds for development as PB2 inhibitors. A receptor-based pharmacophore model was successfully constructed using key amino acid residues for the binding of inhibitors to PB2, provided by the MD simulations. This pharmacophore model suggested that to improve the activity of our active compounds, we should mainly focus on optimizing their existing structures with the aim of increasing their adaptability to the binding site, rather than adding chemical fragments to increase their binding to adjacent sites. This pharmacophore construction method facilitates the creation of a reasonable pharmacophore model without the need to fully understand the structure-activity relationships, and our descriptions provide a useful reference for similar research.
Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Simulação de Dinâmica Molecular , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/química , Pirimidinas/química , Pirróis/química , Relação Estrutura-Atividade , Proteínas Virais/metabolismoRESUMO
The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 µM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 µM and 13.31 ± 1.24 µM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 µM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.
Assuntos
Antivirais/farmacologia , Artemisininas/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Animais , Antimaláricos/farmacologia , COVID-19 , Chlorocebus aethiops , Descoberta de Drogas , Reposicionamento de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Pandemias , SARS-CoV-2 , Células VeroAssuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antimaláricos , Antivirais , Betacoronavirus/efeitos dos fármacos , Cloroquina , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/patogenicidade , Bioensaio , COVID-19 , Chlorocebus aethiops , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , SARS-CoV-2 , Sincalida , Células Vero , Tratamento Farmacológico da COVID-19RESUMO
It is known that lethal viruses profoundly manipulate host metabolism, but how the metabolism alternation affects the immediate host antiviral immunity remains elusive. Here, we report that the O-GlcNAcylation of mitochondrial antiviral-signaling protein (MAVS), a key mediator of interferon signaling, is a critical regulation to activate the host innate immunity against RNA viruses. We show that O-GlcNAcylation depletion in myeloid cells renders the host more susceptible to virus infection both in vitro and in vivo. Mechanistically, we demonstrate that MAVS O-GlcNAcylation is required for virus-induced MAVS K63-linked ubiquitination, thereby facilitating IRF3 activation and IFNß production. We further demonstrate that D-glucosamine, a commonly used dietary supplement, effectively protects mice against a range of lethal RNA viruses, including human influenza virus. Our study highlights a critical role of O-GlcNAcylation in regulating host antiviral immunity and validates D-glucosamine as a potential therapeutic for virus infections.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Imunidade Inata , Infecções por Orthomyxoviridae/imunologia , Processamento de Proteína Pós-Traducional , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Chlorocebus aethiops , Feminino , Glucosamina/metabolismo , Células HEK293 , Células HeLa , Humanos , Interferon beta/genética , Interferon beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Células Mieloides/metabolismo , Células Mieloides/virologia , Transdução de Sinais , Células VeroRESUMO
Hand, foot and mouth disease (HFMD) is a serious, highly contagious disease. HFMD caused by Enterovirus 71 (EV71), results in severe complications and even death. The pivotal role of EV71 3Cpro in the viral life cycle makes it an attractive target for drug discovery and development to treat HFMD. In this study, we identified novel EV71 3Cpro inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3Cpro. The best inhibitor DC07090 exhibited the inhibition potency with an IC50 value of 21.72 ± 0.95 µM without apparent toxicity (CC50 > 200 µM). To explore structure-activity relationship of DC07090, 15 new derivatives were designed, synthesized and evaluated in vitro enzyme assay accordingly. Interestingly, four compounds showed inhibitory activities against EV71 3Cpro and only DC07090 inhibited EV71 replication with an EC50 value of 22.09 ± 1.07 µM. Enzyme inhibition kinetic experiments showed that the compound was a reversible and competitive inhibitor. The Ki value was determined to be 23.29 ± 12.08 µM. Further molecular docking, MD simulation and mutagenesis studies confirmed the binding mode of DC07090 and EV71 3Cpro. Besides, DC07090 could also inhibit coxsackievirus A16 (CVA16) replication with an EC50 value of 27.76 ± 0.88 µM. Therefore, DC07090 represents a new non-peptidyl small molecule inhibitor for further development of antiviral therapy against EV71 or other picornaviruses.
Assuntos
Antivirais/química , Antivirais/farmacologia , Enterovirus Humano A/enzimologia , Oxazóis/química , Oxazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Proteínas Virais/antagonistas & inibidores , Proteases Virais 3C , Antivirais/metabolismo , Sítios de Ligação , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Avaliação Pré-Clínica de Medicamentos , Enterovirus Humano A/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxazóis/metabolismo , Conformação Proteica , Piridinas/metabolismo , Relação Estrutura-Atividade , Interface Usuário-Computador , Proteínas Virais/química , Proteínas Virais/metabolismoRESUMO
Phillyrin was one of the main chemical constituents of the fruit of Forsythia suspensa (Thunb.) Vahl. It showed various bioactivities including antioxidant and anti-inflammatory activities. However, the metabolism of phillyrin remained unknown. This report described the isolation and identification of phase I metabolites of phillyrin in rats. Nine metabolites including six new ones were isolated by various column chromatographies and high-performance liquid chromatography. Their structures were elucidated by extensive spectroscopic analysis. The antiviral activities of phillyrin and the metabolites were evaluated against influenza A (H3N2) virus. Among them, one metabolite M8 showed moderate activity with the IC50 value of 26.39 µM, and three metabolites (M2, M3, M9) showed weak antiviral activities at the concentration of 100 µM. Based on the structures of the metabolites, possible metabolic pathways of phillyrin in rats were also proposed.