RESUMEN
There is growing concern that the severe respiratory disease in birds (avian influenza or 'bird flu') caused by the H5N1 influenza virus, might potentially spread more widely to humans and cause a pandemic. Here we discuss clinical issues related to human infections by the highly pathogenic H5N1 subtype of the avian influenza A virus and make a clinical comparison with recent information obtained from studies of SARS-CoV-2 infection. Firstly, we consider the potential increase in cardiovascular events in humans infected with the H5N1 virus. Like SARS-CoV-2 infection, H5N1 infection may result in endothelial dysfunction and the associated procoagulant and prothrombotic state, and via this mechanism, the infection can potentially increase cardiovascular morbidity, especially in vulnerable individuals with pre-existing cardiovascular disease. Secondly, we discuss the potential beneficial role of statin use, both in the prophylaxis and the treatment of individuals with influenza A(H5N1), as was found favorable for the treatment of COVID-19 caused by SARS-CoV-2 infection.
There is a concern that avian influenza caused by the highly pathogenic avian influenza A(H5N1) virus might potentially spread more widely to humans and result in a pandemicH5N1 infection may result in endothelial dysfunction and via this mechanism, it can potentially increase cardiovascular morbidity and mortality as has occurred with SARS-CoV-2 infection.There is a potential advantage of the use of statins to reduce cardiovascular morbidity and mortality in patients with avian influenza A(H5N1), as has been found in patients suffering from COVID-19.
Asunto(s)
COVID-19 , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Subtipo H5N1 del Virus de la Influenza A , Gripe Humana , Humanos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/prevención & control , Gripe Humana/epidemiología , COVID-19/prevención & control , COVID-19/complicaciones , COVID-19/epidemiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Animales , SARS-CoV-2 , Gripe Aviar/epidemiología , Aves , Pandemias , Tratamiento Farmacológico de COVID-19RESUMEN
Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010-2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor (baloxavir) were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC50s 3- to 4-fold lower than for other subtypes (median IC50: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC50 increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC50 and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC50 (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.
Asunto(s)
Antivirales , Aves , Dibenzotiepinas , Farmacorresistencia Viral , Inhibidores Enzimáticos , Genotipo , Virus de la Influenza A , Gripe Aviar , Neuraminidasa , Oseltamivir , Piridonas , Triazinas , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/genética , Antivirales/farmacología , Gripe Aviar/virología , Animales , Inhibidores Enzimáticos/farmacología , Dibenzotiepinas/farmacología , Farmacorresistencia Viral/genética , Piridonas/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/genética , Virus de la Influenza A/enzimología , Triazinas/farmacología , Oseltamivir/farmacología , Aves/virología , Morfolinas/farmacología , Endonucleasas/antagonistas & inhibidores , Endonucleasas/genética , Endonucleasas/metabolismo , Subtipo H9N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H9N2 del Virus de la Influenza A/genética , Proteínas Virales/genética , Proteínas Virales/antagonistas & inhibidores , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/enzimología , Zanamivir/farmacología , Fenotipo , Humanos , Concentración 50 InhibidoraRESUMEN
Aim: The purpose of this study is to design and synthesize a new series of sulfamethazine derivatives as potent neuraminidase inhibitors. Materials & methods: A sulfamethazine lead compound, ZINC670537, was first identified by structure-based virtual screening technique, then some novel inhibitors X1-X10 based on ZINC670537 were designed and synthesized. Results: Compound X3 exerts the most good potency in inhibiting the wild-type H5N1 NA (IC50 = 6.74 µM) and the H274Y mutant NA (IC50 = 21.09 µM). 150-cavity occupation is very important in determining activities of these inhibitors. The sulfamethazine moiety also plays an important role. Conclusion: Compound X3 maybe regard as a good anti-influenza candidate to preform further study.
[Box: see text].
Asunto(s)
Antivirales , Diseño de Fármacos , Inhibidores Enzimáticos , Subtipo H5N1 del Virus de la Influenza A , Neuraminidasa , Sulfametazina , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , Sulfametazina/farmacología , Sulfametazina/síntesis química , Sulfametazina/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/enzimología , Relación Estructura-Actividad , Humanos , Estructura Molecular , Simulación del Acoplamiento MolecularRESUMEN
Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC50 = 0.13 µM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC50 = 0.44 µM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.
Asunto(s)
Antivirales , Inhibidores Enzimáticos , Neuraminidasa , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Estructura-Actividad , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/enzimología , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Estructura Molecular , Humanos , Simulación de Dinámica Molecular , Relación Dosis-Respuesta a DrogaRESUMEN
Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.
Asunto(s)
Dibenzotiepinas/farmacología , Virus de la Influenza A/efectos de los fármacos , Morfolinas/farmacología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Piridonas/farmacología , Triazinas/farmacología , Células A549 , Animales , Antivirales/farmacología , Quimiocinas/metabolismo , Citocinas/metabolismo , Quimioterapia Combinada , Femenino , Humanos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Oseltamivir/farmacología , Neumonía/tratamiento farmacológico , Análisis de Secuencia , Replicación Viral/efectos de los fármacosRESUMEN
The circulation of avian influenza A viruses in poultry is a public health concern due to the potential transmissibility and severity of these viral infections. Monitoring the susceptibility of these viruses to antivirals is important for developing measures to strengthen the level of preparedness against influenza pandemics. However, drug susceptibility information on these viruses is limited. Here, we determined the susceptibilities of avian influenza A(H5N1), A(H5N2), A(H5N8), A(H7N7), A(H7N9), A(H9N1), and A(H9N2) viruses isolated in Japan to the antivirals approved for use there: an M2 inhibitor (amantadine), neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and RNA polymerase inhibitors (baloxavir and favipiravir). Genotypic methods that detect amino acid substitutions associated with antiviral resistance and phenotypic methods that assess phenotypic viral susceptibility to drugs have revealed that these avian influenza A viruses are susceptible to neuraminidase and RNA polymerase inhibitors. These results suggest that neuraminidase and RNA polymerase inhibitors currently approved in Japan could be a treatment option against influenza A virus infections in humans.
Asunto(s)
Farmacorresistencia Viral , Gripe Aviar , Gripe Humana , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , ARN Polimerasas Dirigidas por ADN , Farmacorresistencia Viral/genética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H7N7 del Virus de la Influenza A/efectos de los fármacos , Subtipo H7N9 del Virus de la Influenza A/efectos de los fármacos , Subtipo H9N2 del Virus de la Influenza A/efectos de los fármacos , Gripe Aviar/epidemiología , Gripe Aviar/virología , Gripe Humana/epidemiología , Gripe Humana/virología , Japón/epidemiología , Neuraminidasa/genética , Neuraminidasa/metabolismo , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Aves de CorralRESUMEN
Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH2 modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1 NAs with IC50 values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, 23d showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment of influenza virus infection.
Asunto(s)
Antivirales/farmacología , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Neuraminidasa/antagonistas & inhibidores , Oseltamivir/farmacología , Animales , Antivirales/química , Antivirales/farmacocinética , Disponibilidad Biológica , Embrión de Pollo , Simulación por Computador , Semivida , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oseltamivir/química , Oseltamivir/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Antiviral short-hairpin RNAs (shRNAs) delivered by recombinant adeno-associated virus (rAAV) were investigated for their potential prophylactic and therapeutic applications related to the influenza A virus (IAV). To express shRNAs efficiently, an H1 promoter was inserted into the commercial rAAV2 system. The modified rAAV2 system could express shRNAs, and the purified rAAV was obtained at levels over 1013 viral genomes/ml and 1010 viral infection units/ml. The shNP-1496-n and shM2-925 delivered by rAAV could inhibit the replication of the H1N1 and H5N1 virus by targeting the conserved regions of the IAV nucleoprotein and matrix 2 genes in MDCK cells. The shNP-1496-n and shM2-925 expressed by rAAV could provide potent and long-term anti-H5N1 virus effects in rAAV-shRNA-enriched MDCK cells. Our findings provide a rational basis for developing RNA interference for the prevention and therapy of IAV infection.
Asunto(s)
Antivirales/farmacología , Dependovirus/genética , Virus de la Influenza A/efectos de los fármacos , ARN Interferente Pequeño/farmacología , Replicación Viral/efectos de los fármacos , Animales , Perros , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Células de Riñón Canino Madin Darby , Proteínas de la Nucleocápside/genética , Regiones Promotoras Genéticas/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas de la Matriz Viral/genética , Proteínas Viroporinas/genéticaRESUMEN
Neuraminidase (NA) is an important target for the treatment of influenza. In this study, a new lead NA inhibitor, 4 (ZINC01121127), was discovered by pharmacophore-based virtual screening and molecular dynamic (MD) simulation. Some novel NA inhibitors containing thiophene ring were synthesized by optimizing the skeleton of the lead compound 4. Compound 4b had the most potent inhibitory activity against NA (IC50 = 0.03 µM), which was better than the positive control oseltamivir carboxylate (IC50 = 0.06 µM). 4b (EC50 = 1.59 µM) also exhibits excellent antiviral activity against A/chicken/Hubei/327/2004 (H5N1-DW), which is superior to the reference drug OSC (EC50 = 5.97 µM). Molecular docking study shows that the thiophene moiety plays an essential role in compound 4b, which can bind well to the active site of NA. The good activity of 4b may be also ascribed to the extending of quinoline ring into the 150-cavity. The results of this study may provide an insightful help for the development of new NA inhibitors.
Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Neuraminidasa/antagonistas & inhibidores , Tiofenos/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Subtipo H5N1 del Virus de la Influenza A/enzimología , Células de Riñón Canino Madin Darby/efectos de los fármacos , Células de Riñón Canino Madin Darby/virología , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Neuraminidasa/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
Influenza A viruses are serious zoonotic pathogens that continuously cause pandemics in several animal hosts, including birds, pigs, and humans. Indole derivatives containing an indole core framework have been extensively studied and developed to prevent and/or treat viral infection. This study evaluated the anti-influenza activity of several indole derivatives, including 3-indoleacetonitrile, indole-3-carboxaldehyde, 3-carboxyindole, and gramine, in A549 and MDCK cells. Among these compounds, 3-indoleacetonitrile exerts profound antiviral activity against a broad spectrum of influenza A viruses, as tested in A549 cells. Importantly, in a mouse model, 3-indoleacetonitrile with a non-toxic concentration of 20 mg/kg effectively reduced the mortality and weight loss, diminished lung virus titers, and alleviated lung lesions of mice lethally challenged with A/duck/Hubei/WH18/2015 H5N6 and A/Puerto Rico/8/1934 H1N1 influenza A viruses. The antiviral properties enable the potential use of 3-indoleacetonitrile for the treatment of IAV infection.
Asunto(s)
Antivirales/farmacología , Indoles/farmacología , Indoles/uso terapéutico , Virus de la Influenza A/efectos de los fármacos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Células A549 , Animales , Antivirales/uso terapéutico , Antivirales/toxicidad , Perros , Femenino , Humanos , Indoles/toxicidad , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/fisiología , Virus de la Influenza A/fisiología , Pulmón/patología , Pulmón/virología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Sulfuros/farmacología , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Pentacyclic triterpenes and cardenolides were isolated from Acokanthera oblongifolia leaves. Their chemical structures were determined based on comprehensive 1D and 2D NMR spectroscopy. Their MIC was determined against 12 microorganisms. Their exerted cytotoxicity on the immortalized normal cells, hTERT-RPE1 was assessed by the sulforhodamine-B assay. The viral inhibitory effects of compounds against Newcastle disease virus (NDV) and H5N1 influenza virus IV were evaluated. Four in vitro antioxidant assays were performed in comparison with BHT and trolox and a weak activity was exhibited. Acovenoside A was with potent against H5N1-IV and NDV with IC50 ≤ 3.2 and ≤ 2.1 µg/ml and SI values of 93.75 and 95.23%, respectively, in comparison to ribavirin. Its CC50 record on Vero cells was > 400 and 200 µg/ml, respectively. Acobioside A was the most active compound against a broad range of microbes while Pseudomonas aeruginosa was the most sensitive. Its MIC (0.07 µg/ml) was 1/100-fold of the recorded CC50 (7.1 µg/ml/72 h) against hTERT-RPE1. The molecular docking of compounds on human DNA topoisomerase I (Top1-DNA) and IV glycoprotein hemagglutinin were studied using MOE program. This study has introduced the cardenolides rather than triterpenoids with the best docking score and binding interaction with the active site of the studied proteins.
Asunto(s)
Antibacterianos/farmacología , Antivirales/farmacología , Apocynaceae/química , Cardenólidos/farmacología , Triterpenos Pentacíclicos/farmacología , Hojas de la Planta/química , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antivirales/química , Antivirales/aislamiento & purificación , Cardenólidos/química , Cardenólidos/aislamiento & purificación , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Células Epiteliales/efectos de los fármacos , Humanos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Simulación del Acoplamiento Molecular , Estructura Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Epitelio Pigmentado de la Retina/citología , Células VeroRESUMEN
Coffee has been studied for its health benefits, including prevention of several chronic diseases, such as type 2 diabetes mellitus, cancer, Parkinson's, and liver diseases. Chlorogenic acid (CGA), an important component in coffee beans, was shown to possess antiviral activity against viruses. However, the presence of caffeine in coffee beans may also cause insomnia and stomach irritation, and increase heart rate and respiration rate. These unwanted effects may be reduced by decaffeination of green bean Arabica coffee (GBAC) by treatment with dichloromethane, followed by solid-phase extraction using methanol. In this study, the caffeine and chlorogenic acid (CGA) level in the coffee bean from three different areas in West Java, before and after decaffeination, was determined and validated using HPLC. The results showed that the levels of caffeine were reduced significantly, with an order as follows: Tasikmalaya (2.28% to 0.097% (97 ppm), Pangalengan (1.57% to 0.049% (495 ppm), and Garut (1.45% to 0.00002% (0.2 ppm). The CGA levels in the GBAC were also reduced as follows: Tasikmalaya (0.54% to 0.001% (118 ppm), Pangalengan (0.97% to 0.0047% (388 ppm)), and Garut (0.81% to 0.029% (282 ppm). The decaffeinated samples were then subjected to the H5N1 neuraminidase (NA) binding assay to determine its bioactivity as an anti-influenza agent. The results show that samples from Tasikmalaya, Pangalengan, and Garut possess NA inhibitory activity with IC50 of 69.70, 75.23, and 55.74 µg/mL, respectively. The low level of caffeine with a higher level of CGA correlates with their higher levels of NA inhibitory, as shown in the Garut samples. Therefore, the level of caffeine and CGA influenced the level of NA inhibitory activity. This is supported by the validation of CGA-NA binding interaction via molecular docking and pharmacophore modeling; hence, CGA could potentially serve as a bioactive compound for neuraminidase activity in GBAC.
Asunto(s)
Cafeína/análisis , Ácido Clorogénico/análisis , Coffea/química , Subtipo H5N1 del Virus de la Influenza A/enzimología , Cloruro de Metileno/farmacología , Neuraminidasa/antagonistas & inhibidores , Cafeína/efectos adversos , Cafeína/farmacología , Ácido Clorogénico/química , Ácido Clorogénico/farmacología , Cromatografía Líquida de Alta Presión , Coffea/efectos de los fármacos , Manipulación de Alimentos , Humanos , Subtipo H5N1 del Virus de la Influenza A/química , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Concentración 50 Inhibidora , Modelos Moleculares , Simulación del Acoplamiento Molecular , Unión Proteica , Extracción en Fase Sólida , Proteínas Virales/antagonistas & inhibidoresRESUMEN
Highly pathogenic avian influenza viruses (HPAIVs) pose a significant threat to human health, with high mortality rates, and require effective vaccines. We showed that, harnessed with novel RNA-mediated chaperone function, hemagglutinin (HA) of H5N1 HPAIV could be displayed as an immunologically relevant conformation on self-assembled chimeric nanoparticles (cNP). A tri-partite monomeric antigen was designed including: i) an RNA-interaction domain (RID) as a docking tag for RNA to enable chaperna function (chaperna: chaperone + RNA), ii) globular head domain (gd) of HA as a target antigen, and iii) ferritin as a scaffold for 24 mer-assembly. The immunization of mice with the nanoparticles (~46 nm) induced a 25-30 fold higher neutralizing capacity of the antibody and provided cross-protection from homologous and heterologous lethal challenges. This study suggests that cNP assembly is conducive to eliciting antibodies against the conserved region in HA, providing potent and broad protective efficacy.
Asunto(s)
Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Vacunas contra la Influenza/inmunología , Gripe Aviar/inmunología , ARN/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Aves/virología , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/uso terapéutico , Humanos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Vacunas contra la Influenza/química , Vacunas contra la Influenza/uso terapéutico , Gripe Aviar/prevención & control , Gripe Aviar/virología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Pandemias , ARN/genética , ARN/uso terapéuticoRESUMEN
Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.
Asunto(s)
Epigenómica , Inmunidad/genética , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Análisis de la Célula Individual , Transcripción Genética , Vacunación , Adolescente , Adulto , Antibacterianos/farmacología , Antígenos CD34/metabolismo , Antivirales/farmacología , Reprogramación Celular , Cromatina/metabolismo , Citocinas/biosíntesis , Combinación de Medicamentos , Femenino , Regulación de la Expresión Génica , Histonas/metabolismo , Humanos , Inmunidad Innata/genética , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Interferón Tipo I/metabolismo , Masculino , Células Mieloides/metabolismo , Polisorbatos/farmacología , Escualeno/farmacología , Receptores Toll-Like/metabolismo , Factor de Transcripción AP-1/metabolismo , Transcriptoma/genética , Adulto Joven , alfa-Tocoferol/farmacologíaRESUMEN
In this study, 2-hydroxypropyltrimethyl ammonium chloride chitosan (HTCC)-based hydrogel was devised as a mucosal adjuvant for H5N1 vaccine. Aimed to investigate the structure activity relationship between HTCC hydrogel and immune response, we prepared a series of HTCC hydrogel with defined quaternization degrees (DQs, 0%, 21%, 41%, 60%, 80%). Results suggested that with DQ increasing, the positive charge and gelation time of HTCC hydrogel increased but the viscosity decreased. We applied in vivo imaging system and found that the moderate DQ 41% prolonged antigen residence time in nasal cavity, resulting in the most potent systemic responses (IgG, IgG1, IgG2a, HI). While, the lowest DQ 0% produced the best mucosal IgA antibody responses, most likely due to the closer contact with mucosa. Furthermore, the influence of animal gender was also discussed. These data add to the growing understanding of the relationship between physicochemical features of chitosan-based hydrogel and how they influence the immune responses.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Quitosano/análogos & derivados , Hidrogeles/farmacología , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/química , Administración Intranasal , Animales , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Quitosano/administración & dosificación , Quitosano/química , Quitosano/farmacología , Femenino , Hidrogeles/administración & dosificación , Hidrogeles/química , Inmunidad/efectos de los fármacos , Inmunidad Mucosa/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Masculino , Ratones Endogámicos BALB C , Mucosa Nasal/virología , Compuestos de Amonio Cuaternario/administración & dosificación , Compuestos de Amonio Cuaternario/química , Ratas Sprague-Dawley , Factores Sexuales , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Even though antiviral drugs against H5N1 flu infection are accessible, they are still limited by antiviral drug resistance and unfavorable side effects. Thus, this work tested the action of epigallocatechin gallate (EGCG) co-administered with both zinc (II) ions and silver nanoparticles (AgNPs). MATERIALS AND METHODS: EGCG was used with both zinc sulfate (zinc II) and silver nanoparticles to test their antiviral activities against avian flu subtype H5N1 in embryonated SPF eggs. The MTS test was used to determine the cytotoxicity. RESULTS: Zinc sulfate (1.5 mg/mL) and silver nanoparticles showed comparable potentiated antiviral action with EGCG (50 µM) against the H5N1 avian flu virus. They decreased the log titer infection by up to 5.7 and 5.6 fold separately with critical antiviral activity (p<0.01). In most cases, an illustrative relationship was seen when H5N1 was tested with EGCG and various concentrations of zinc sulfate. The EGCG-AgNPs with zinc sulfate were observed to have very strong antiviral activity (p<0.001) against the H5N1 avian influenza virus with a reduction in the log titer of the virus by up to 7.6 times. No cytotoxicity was recognized. CONCLUSIONS: The potentiated antiviral activity of EGCG by co-administering it with zinc II and AgNPs indicates potential as a multi-activity novel topical therapeutic agent against H5N1 flue. This mix makes the adaptation of the virus difficult, which helps to reduce infection resistance.
Asunto(s)
Antivirales/farmacología , Catequina/análogos & derivados , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Nanopartículas del Metal/química , Plata/farmacología , Sulfato de Zinc/farmacología , Animales , Antivirales/química , Catequina/química , Catequina/farmacología , Células Cultivadas , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Plata/química , Células Vero , Sulfato de Zinc/químicaRESUMEN
BACKGROUND: The COVID-19 pandemic is requesting highly effective protective personnel equipment, mainly for healthcare professionals. However, the current demand has exceeded the supply chain and, consequently, shortage of essential medical materials, such as surgical masks. Due to these alarming limitations, it is crucial to develop effective means of disinfection, reusing, and thereby applying antimicrobial shielding protection to the clinical supplies. PURPOSE: Therefore, in this work, we developed a novel, economical, and straightforward approach to promote antimicrobial activity to surgical masks by impregnating silver nanoparticles (AgNPs). METHODS: Our strategy consisted of fabricating a new alcohol disinfectant formulation combining special surfactants and AgNPs, which is demonstrated to be extensively effective against a broad number of microbial surrogates of SARS-CoV-2. RESULTS: The present nano-formula reported a superior microbial reduction of 99.999% against a wide number of microorganisms. Furthermore, the enveloped H5N1 virus was wholly inactivated after 15 min of disinfection. Far more attractive, the current method for reusing surgical masks did not show outcomes of detrimental amendments, suggesting that the protocol does not alter the filtration effectiveness. CONCLUSION: The nano-disinfectant provides a valuable strategy for effective decontamination, reuse, and even antimicrobial promotion to surgical masks for frontline clinical personnel.
Asunto(s)
Antiinfecciosos/farmacología , Desinfectantes/farmacología , Máscaras , Nanopartículas del Metal/química , Plata/farmacología , Animales , Antiinfecciosos/administración & dosificación , Antiinfecciosos/química , Antivirales/química , Antivirales/farmacología , COVID-19/prevención & control , COVID-19/transmisión , Embrión de Pollo , Desinfectantes/administración & dosificación , Desinfectantes/química , Desinfección/métodos , Dispersión Dinámica de Luz , Equipo Reutilizado , Humanos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Máscaras/virología , Nanopartículas del Metal/administración & dosificación , Pruebas de Sensibilidad Microbiana , Plata/química , Espectroscopía Infrarroja por Transformada de Fourier , Textiles , Difracción de Rayos XRESUMEN
A metal nanoparticle composite, namely TPNT1, which contains Au-NP (1 ppm), Ag-NP (5 ppm), ZnO-NP (60 ppm) and ClO2 (42.5 ppm) in aqueous solution was prepared and characterized by spectroscopy, transmission electron microscopy, dynamic light scattering analysis and potentiometric titration. Based on the in vitro cell-based assay, TPNT1 inhibited six major clades of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with effective concentration within the range to be used as food additives. TPNT1 was shown to block viral entry by inhibiting the binding of SARS-CoV-2 spike proteins to the angiotensin-converting enzyme 2 (ACE2) receptor and to interfere with the syncytium formation. In addition, TPNT1 also effectively reduced the cytopathic effects induced by human (H1N1) and avian (H5N1) influenza viruses, including the wild-type and oseltamivir-resistant virus isolates. Together with previously demonstrated efficacy as antimicrobials, TPNT1 can block viral entry and inhibit or prevent viral infection to provide prophylactic effects against both SARS-CoV-2 and opportunistic infections.
Asunto(s)
Oro/farmacología , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H5N1 del Virus de la Influenza A/fisiología , SARS-CoV-2/fisiología , Plata/farmacología , Óxido de Zinc/farmacología , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/química , Antivirales/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Aditivos Alimentarios/farmacología , Oro/química , Células HEK293 , Humanos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Nanopartículas del Metal/química , Nanocompuestos/química , Oseltamivir/farmacología , Tamaño de la Partícula , Unión Proteica/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Plata/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacos , Óxido de Zinc/químicaRESUMEN
This study describes the effective attack of oligonucleotides on the viral genome of highly pathogenic H5N1 influenza A virus (IAV) in vivo using for the first time the new delivery system consisting of biocompatible low-toxic titanium dioxide nanoparticles and immobilized polylysine-containing oligonucleotides with the native (ODN) and partially modified (ODNm) internucleotide bonds. Intraperitoneal injection of the TiO2â¢PL-ODN nanocomposite provided 65-70% survival of mice, while intraperitoneal or oral administration of TiO2â¢PL-ODNm was somewhat more efficient (~80% survival). The virus titer in the lung was reduced by two-three orders of magnitude. The nanocomposites are nontoxic to mice under the used conditions. TiO2 nanoparticles, unbound ODN, and the nanocomposite bearing the random oligonucleotide showed an insignificant protective effect, which indicates the ability of targeted oligonucleotides delivered in mice in the nanocomposites to site-specifically interact with complementary RNAs. The protection of oligonucleotides in nanocomposites by TiO2 nanoparticles and partial modification of the internucleotide bonds provides a continued presence of oligonucleotides in the body for the effective and specific action on the viral RNA. The proposed oligonucleotide delivery system can claim not only to effectively inhibit IAV genes but also to turn off other genes responsible for diseases caused by nucleic acids.
Asunto(s)
Antivirales/administración & dosificación , Portadores de Fármacos/química , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Oligodesoxirribonucleótidos Antisentido/administración & dosificación , Administración Oral , Animales , Modelos Animales de Enfermedad , Perros , Femenino , Genoma Viral/efectos de los fármacos , Humanos , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/virología , Inyecciones Intraperitoneales , Células de Riñón Canino Madin Darby , Masculino , Ratones , Nanocompuestos/química , ARN Viral/antagonistas & inhibidores , Titanio/química , Carga Viral/efectos de los fármacosRESUMEN
Novel class of amino pyrimidine thioglycoside derivatives were designed from sodium 2-cyano-3-(arylamino)prop-1-ene-1,1-bis(thiolate) 1a-d and guanidine hydrochloride 2 to afford the corresponding sodium 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate 3a-d, which in coupling with peracylated α-D-gluco- and galactopyranosyl bromides 5a,b in DMF gave the corresponding pyrimidine thioglycosides 6a-h. Acidification of 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate salts 3a-d with hydrochloric acid formed the corresponding pyrimidine-4-thioles 4a-d. The latter were stirred with peracetylated halo sugars α-D-gluco- and galacto-pyranosyl bromides in sodium hydride and DMF to yield the pyrimidine thioglycosides 6a-h. Deacetylation of the pyrimidine thioglycosides gave the corresponding free pyrimidine thioglycosides 7a-h. The compounds were characterized by 13C NMR, 1H NMR, and IR. The pyrimidine thioglycosides 6a-h and free pyrimidine thioglycosides 7a-h were tested against H5N1 virus strain and exhibited high to moderate activity.