RESUMEN
Transcription of viral mRNA in cells infected with influenza viruses involves capturing and cleaving the first 10-20 nucleotides of 5' capped host mRNAs to be used as primers in viral RNA synthesis. A newly developed inhibitor of the viral endonuclease responsible for this cap-snatching shows therapeutic efficacy for the treatment of influenza. To view this Bench to Bedside, open or download the PDF.
Asunto(s)
Gripe Humana/tratamiento farmacológico , Oxazinas/farmacología , Oxazinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Tiepinas/farmacología , Tiepinas/uso terapéutico , Triazinas/farmacología , Triazinas/uso terapéutico , Dibenzotiepinas , Endonucleasas/genética , Humanos , Morfolinas , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/patogenicidad , Piridonas , Caperuzas de ARN/genética , ARN Mensajero/genética , ARN Viral/genética , Proteínas Virales/genéticaRESUMEN
Drug resistance is prevalent across many diseases, rendering therapies ineffective with severe financial and health consequences. Rather than accepting resistance after the fact, proactive strategies need to be incorporated into the drug design and development process to minimize the impact of drug resistance. These strategies can be derived from our experience with viral disease targets where multiple generations of drugs had to be developed to combat resistance and avoid antiviral failure. Significant efforts including experimental and computational structural biology, medicinal chemistry, and machine learning have focused on understanding the mechanisms and structural basis of resistance against direct-acting antiviral (DAA) drugs. Integrated methods show promise for being predictive of resistance and potency. In this review, we give an overview of this research for human immunodeficiency virus type 1, hepatitis C virus, and influenza virus and the lessons learned from resistance mechanisms of DAAs. These lessons translate into rational strategies to avoid resistance in drug design, which can be generalized and applied beyond viral targets. While resistance may not be completely avoidable, rational drug design can and should incorporate strategies at the outset of drug development to decrease the prevalence of drug resistance.
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Antivirales/química , Inhibidores Enzimáticos/química , Preparaciones Farmacéuticas/química , Proteínas Virales/química , Virosis/tratamiento farmacológico , Antivirales/metabolismo , Antivirales/farmacología , Biología Computacional , Diseño de Fármacos , Farmacorresistencia Viral , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , VIH-1/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Aprendizaje Automático , Mutación , Orthomyxoviridae/efectos de los fármacos , Preparaciones Farmacéuticas/metabolismo , Unión Proteica , Transducción de Señal , Relación Estructura-ActividadRESUMEN
The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.
Asunto(s)
Antivirales/farmacología , Coronavirus/efectos de los fármacos , Filoviridae/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Complejos Multiproteicos/metabolismo , Orthomyxoviridae/efectos de los fármacos , Línea Celular , Genes Supresores , Modelos Moleculares , Terapia Molecular Dirigida , Unión Proteica , ARN Interferente Pequeño/metabolismo , ARN Viral/genética , ARN Viral/metabolismo , Saccharomyces cerevisiae/genética , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Homologues of the Oscillatoria agardhii agglutinin (OAA) lectins contain a sequence repeat of â¼66 amino acids, with the number of tandem repeats varying across family members. OAA homologues bind high-mannose glycans on viral surface proteins, thereby interfering with viral entry into host cells. As such, OAA homologues have potential utility as antiviral agents, but a more detailed understanding of their structure-function relationships would enable us to develop improved constructs. Here, we determined the X-ray crystal structure of free and glycan-bound forms of Pseudomonas taiwanensis lectin (PTL), an OAA-family lectin consisting of two tandem repeats. Like other OAA-family lectins, PTL exhibited a ß-barrel-like structure with two symmetrically positioned glycan-binding sites at the opposite ends of the barrel. Upon glycan binding, the conformation of PTL undergoes a more significant change than expected from previous OAA structural analysis. Moreover, the electron density of the bound glycans suggested that the binding affinities are different at the two binding sites. Next, based on analysis of these structures, we used site-specific mutagenesis to create PTL constructs expected to increase the population with a conformation suitable for glycan binding. The engineered PTLs were examined for their antiviral activity against the influenza virus. Interestingly, some exhibited stronger activity compared with that of the parent PTL. We propose that our approach is effective for the generation of potential microbicides with enhanced antiviral activity.
Asunto(s)
Antivirales/metabolismo , Antivirales/farmacología , Lectinas/metabolismo , Lectinas/farmacología , Polisacáridos/metabolismo , Ingeniería de Proteínas , Antivirales/química , Cristalografía por Rayos X , Lectinas/química , Lectinas/genética , Modelos Moleculares , Orthomyxoviridae/efectos de los fármacos , Unión Proteica , Conformación Proteica en Lámina betaRESUMEN
Production of broadly-reactive antibodies is critical for universal immunodiagnosis of rapidly-evolving influenza viruses. Most monoclonal antibodies (mAbs) are generated in mice using the hybridoma technology which involves labor- and time-consuming screening and low yield issues. In this study, a recombinant antibody based on a broadly-reactive mAb against the hemagglutinin (HA) stalk of H7N9 avian influenza virus was expressed in CHO cells and its biological characteristics, cross-reactivity and epitope recognition were identified. The variable genes of the parental antibody were amplified and cloned into the antibody-expressing plasmids containing the constant genes of murine IgG1. The recombinant antibody was expressed in high yield and purity in CHO cells and showed similar features to the parental antibody, including negative hemagglutination inhibition activity against H7N9 virus and high binding activity with the H7N9 HA protein. Notably, the recombinant antibody exhibited a broad reactivity with different influenza subtypes belonging to group 1 and group 2, which was associated with its recognition of a highly-conserved epitope in the stalk, as observed for the parental antibody. Our results suggest that cell-based antibody expression system can be utilized as an important alternative to the hybridoma technology for antibody production for influenza virus diagnostics.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/farmacología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Orthomyxoviridae/efectos de los fármacos , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/aislamiento & purificación , Células CHO , Cricetinae , Cricetulus , Reacciones Cruzadas , Expresión Génica , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Subtipo H7N9 del Virus de la Influenza A/genética , Subtipo H7N9 del Virus de la Influenza A/inmunología , Gripe Humana/virología , Ratones , Orthomyxoviridae/clasificación , Orthomyxoviridae/inmunologíaRESUMEN
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.
Asunto(s)
COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Predisposición Genética a la Enfermedad , Gripe Humana/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Antivirales/uso terapéutico , Variación Biológica Individual , COVID-19/genética , COVID-19/virología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/virología , Expresión Génica , Humanos , Inmunidad Innata , Factores Inmunológicos/uso terapéutico , Gripe Humana/tratamiento farmacológico , Gripe Humana/genética , Gripe Humana/virología , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/inmunología , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/genética , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/efectos de los fármacos , Virus Sincitiales Respiratorios/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , SARS-CoV-2/clasificación , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
In a screening using our unique natural product library, the C-nucleoside antibiotic formycin A, which exerts strong anti-influenza virus activity, was rediscovered. Aiming to develop a new type of anti-influenza virus drug, we synthesized new derivatives of formycin and evaluated its anti-influenza virus activity. Structural modifications were focused on the base moiety and sugar portion, respectively, and >40 novel formycin derivatives were synthesized. Modification of the C-7 position of the pyrazolopyrimidine ring strongly contributed to improve the activity. In particular, excellent anti-influenza virus activity was observed in the NHMe (10), SMe (12), and SeMe (15) derivatives, in which heteroatoms were introduced. In addition, in the modification of the sugar moiety, the presence of a hydroxyl group and its stereochemistry greatly affected both the expression and intensity of the activity. Furthermore, the evaluation results of the 7-SEt derivative (29) and the 2'-modified derivative (59) suggested that structural modifications may reduce cytotoxicity.
Asunto(s)
Antivirales/farmacología , Formicinas/farmacología , Orthomyxoviridae/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Formicinas/síntesis química , Formicinas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Neuraminidase (NA) is an important target in the development of anti-influenza virus drugs. Compounds containing 1,3, 4-oxadiazole heterocycles have good biological activity and have been proved to have wide applications in antibacterial and antiviral drugs. In this paper, a series of novel 1, 3, 4-oxadiazole neuraminidase inhibitors (6a-6l) were designed and synthesized and their inhibitory activities of NA was tested in vitro. The results displayed that compound 6d exerts the best inhibitory activity (IC50 = 0.027 µM), which was obviously lower than that of oseltamivir carboxylate (OSC) (IC50 = 0.082 µM). Molecular docking analysis showed that the 1, 3, 4-oxadiazole heterocycle plays crucial part in compound 6d, and it can interact with the key arginine triad (Arg118, Arg292 and Arg 371) at the NA S1 site. The good efficacy of 6d may also be attributed to the extension of the substituted aniline ring to the 150-cavitiy. The theoretical and experimental results may provide reference for development of new anti-influenza drugs.
Asunto(s)
Antivirales/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Neuraminidasa/antagonistas & inhibidores , Orthomyxoviridae/efectos de los fármacos , Oxadiazoles/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Neuraminidasa/metabolismo , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-ActividadAsunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Desarrollo de Medicamentos/tendencias , Pandemias , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/administración & dosificación , Alanina/análogos & derivados , Alanina/uso terapéutico , Animales , Antivirales/farmacología , Aves/virología , COVID-19/virología , Ensayos Clínicos como Asunto , Coronavirus/clasificación , Coronavirus/efectos de los fármacos , Infecciones por Coronavirus/epidemiología , Citidina/administración & dosificación , Citidina/análogos & derivados , Citidina/síntesis química , Citidina/uso terapéutico , Industria Farmacéutica/tendencias , Europa (Continente) , Humanos , Hidroxilaminas/administración & dosificación , Hidroxilaminas/síntesis química , Hidroxilaminas/uso terapéutico , Indoles/administración & dosificación , Indoles/uso terapéutico , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Leucina/administración & dosificación , Leucina/uso terapéutico , Orthomyxoviridae/efectos de los fármacos , Pirrolidinonas/administración & dosificación , Pirrolidinonas/uso terapéutico , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/epidemiología , Reserva Estratégica , Estados UnidosRESUMEN
New therapeutic strategies targeting influenza are actively sought due to limitations in current drugs available. Host-directed therapy is an emerging concept to target host functions involved in pathogen life cycles and/or pathogenesis, rather than pathogen components themselves. From this perspective, we focused on an essential host partner of influenza viruses, the RED-SMU1 splicing complex. Here, we identified two synthetic molecules targeting an α-helix/groove interface essential for RED-SMU1 complex assembly. We solved the structure of the SMU1 N-terminal domain in complex with RED or bound to one of the molecules identified to disrupt this complex. We show that these compounds inhibiting RED-SMU1 interaction also decrease endogenous RED-SMU1 levels and inhibit viral mRNA splicing and viral multiplication, while preserving cell viability. Overall, our data demonstrate the potential of RED-SMU1 destabilizing molecules as an antiviral therapy that could be active against a wide range of influenza viruses and be less prone to drug resistance.
Asunto(s)
Antivirales/farmacología , Proteínas Cromosómicas no Histona/metabolismo , Citocinas/metabolismo , Orthomyxoviridae/efectos de los fármacos , Factores de Empalme de ARN/metabolismo , Células A549 , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Citocinas/química , Citocinas/genética , Células HEK293 , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Orthomyxoviridae/patogenicidad , Unión Proteica/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Empalme del ARN , Factores de Empalme de ARN/química , Factores de Empalme de ARN/genética , Empalmosomas/efectos de los fármacosRESUMEN
Host cell lipids play a pivotal role in the pathogenesis of respiratory virus infection. However, a direct comparison of the lipidomic profile of influenza virus and rhinovirus infections is lacking. In this study, we first compared the lipid profile of influenza virus and rhinovirus infection in a bronchial epithelial cell line. Most lipid features were downregulated for both influenza virus and rhinovirus, especially for the sphingomyelin features. Pathway analysis showed that sphingolipid metabolism was the most perturbed pathway. Functional study showed that bacterial sphingomyelinase suppressed influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, but promoted rhinovirus replication. These findings suggest that sphingomyelin pathway can be a potential target for antiviral therapy, but should be carefully evaluated as it has opposite effects on different respiratory viruses. Furthermore, the differential effect of sphingomyelinase on rhinovirus and influenza virus may explain the interference between rhinovirus and influenza virus infection.
Asunto(s)
Orthomyxoviridae/efectos de los fármacos , Rhinovirus/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Esfingomielinas/farmacología , Animales , Enfermedades Bronquiales/virología , Línea Celular , Perros , Células Epiteliales/virología , Humanos , Gripe Humana , Lipidómica , Células de Riñón Canino Madin Darby , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Esfingomielina Fosfodiesterasa , Replicación Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
Influenza is an acute viral respiratory infection that affects all age groups and is associated with high mortality during pandemics, epidemics, and sporadic outbreaks. Nearly 10% of the world's population is affected by influenza annually, with about half a million deaths each year. Influenza vaccination is the most effective method for preventing influenza infection and its complications. The influenza vaccine's efficacy varies each season based on the circulating influenza strains and vaccine uptake rates. Currently, three antiviral drugs targeting the influenza virus surface glycoprotein neuraminidase are available for treatment and prophylaxis of disease. Given the significant burden of influenza infection globally, this review is focused on the latest findings in the etiology, epidemiology, transmission, clinical manifestation, diagnosis, prevention, and treatment of influenza.
Asunto(s)
Antivirales/uso terapéutico , Gripe Humana/epidemiología , Gripe Humana/transmisión , Orthomyxoviridae/patogenicidad , Humanos , Vacunas contra la Influenza/inmunología , Gripe Humana/diagnóstico , Gripe Humana/tratamiento farmacológico , Neuraminidasa/antagonistas & inhibidores , Orthomyxoviridae/efectos de los fármacos , Pandemias , VacunaciónRESUMEN
Essential oils and their chemical constituents have been reported with well documented antimicrobial effects against a range of bacterial, fungal and viral pathogens. By definition, essential oils are a complex mixture of volatile organic compounds which are synthesized naturally in different parts of the plant as part of plants secondary metabolism. The chemical composition of the essential oils is dominated by the presence of a range of compounds including phenolics, terpenoids, aldehydes, ketones, ethers, epoxides and many others inferring that essential oils must be effective against a wide range of pathogens. This review article mainly focuses on the antiviral potential of essential oils and their chemical constituents especially against influenza and coronaviruses. Essential oils have been screened against several pathogenic viruses, including influenza and other respiratory viral infections. The essential oils of cinnamon, bergamot, lemongrass, thyme, lavender have been reported to exert potent antiviral effects against influenza type A virus. The essential oil of Citrus reshni leaves has been shown to be effective against H5N1 virus. The essential oil of Lippia species at a concentration of 11.1 µg/mL has been shown to induce 100% inhibition of yellow fever virus in Vero cells. Essential oils and oleoresins have been shown through in vitro and in vivo experiments to induce antiviral effects against Coronavirus infectious bronchitis virus. A study reported 221 phytochemical compounds and essential oils to be effective against severe acute respiratory syndrome associated coronavirus (SARS-CoV) using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. The main mechanism of antiviral effects of essential oils has been found to cause capsid disintegration and viral expansion which prevents the virus to infect host cells by adsorption via the capsid. Essential oils also inhibit hemagglutinin (an important membrane protein of various viruses) of certain viruses; this membrane protein allows the virus to enter the host cell. Many essential oils and their components could inhibit the late stages of viral life cycle by targeting the redox signalling pathway. Essential oils of Thymus vulgaris, cymbopogon citratus and Rosmarinus officinalis have been found to destabilize the Tat/TAR-RNA complex of HIV-1 virus, this complex being essential for HIV-1 replication. Being lipophilic in nature, essential oils can penetrate viral membranes easily leading to membrane disintegration. The current comprehensive review will facilitate researchers to find chemical entities from plant sources as possible inhibitory agents against various viruses.
Asunto(s)
Antivirales/farmacología , Coronavirus/efectos de los fármacos , Aceites Volátiles/farmacología , Orthomyxoviridae/efectos de los fármacos , Antivirales/química , Humanos , Aceites Volátiles/química , SARS-CoV-2/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
A new series of N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)carboxamides have been designed, synthesized and evaluated as antiviral agents. The compounds were prepared by condensation of 2-methylfuran-3-carbohydrazide, appropriate carbonyl compounds and sulfanyl acids. The new molecules were characterized by IR, 1H NMR, 13C NMR, mass spectrometry and elemental analysis. Six analogues proved to be active against influenza A/H3N2 virus, the two most protent analogues, 3c and 3d, having an EC50 value of about 1 µM. These findings help to define the SAR of spirothiazolidinone-based inhibitors of the influenza virus membrane fusion process.
Asunto(s)
Antivirales/farmacología , Diseño de Fármacos , Furanos/farmacología , Orthomyxoviridae/efectos de los fármacos , Compuestos de Espiro/farmacología , Tiazolidinedionas/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Furanos/química , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-Actividad , Tiazolidinedionas/síntesis química , Tiazolidinedionas/químicaRESUMEN
Seasonal influenza A and B viruses represent a global concern. Antiviral drugs are crucial to treat severe influenza in high-risk patients and prevent virus spread in case of a pandemic. The emergence of viruses showing drug resistance, in particular for the recently licensed polymerase inhibitor baloxavir marboxil, drives the need for developing alternative antivirals. The endonuclease activity residing in the N-terminal domain of the polymerase acidic protein (PAN) is crucial for viral RNA synthesis and a validated target for drug design. Its function can be impaired by molecules bearing a metal-binding pharmacophore (MBP) able to coordinate the two divalent metal ions in the active site. In the present work, the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold is explored for the inhibition of influenza virus PA endonuclease. The structure-activity relationship was analysed by modifying the substituents on the lipophilic moiety linked to the MBP. The new compounds exhibited nanomolar inhibitory activity in a FRET-based enzymatic assay, and a few compounds (15-17, 21) offered inhibition in the micromolar range, in a cell-based influenza virus polymerase assay. When investigated against a panel of PA-mutant forms, compound 17 was shown to retain full activity against the baloxavir-resistant I38T mutant. This was corroborated by docking studies providing insight into the binding mode of this novel class of PA inhibitors.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Isoindoles/farmacología , Orthomyxoviridae/efectos de los fármacos , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Isoindoles/síntesis química , Isoindoles/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Orthomyxoviridae/enzimología , ARN Polimerasa Dependiente del ARN/metabolismo , Relación Estructura-Actividad , Proteínas Virales/metabolismoRESUMEN
A lactic acid bacterial strain, Lactobacillus plantarum SN35N, which has been isolated from the pear, secretes negatively charged acidic exopolysaccharide (EPS) to outside cells. We have previously found that the SN35N-derived acidic EPS inhibits the catalytic activity of hyaluronidase (EC 3.2.1.35) promoting inflammation. The aim of this study is to find other health benefits of EPS. EPS has been found to exhibit an inhibitory effect against the influenza virus (Alphainfluenzavirus Influenza A virus) and feline calicivirus (Vesivirus Feline calicivirus), which is recognized as a model of norovirus. Although more studies on the structure-function relationship of EPSs are needed, SN35N-derived EPS is a promising lead for developing not only anti-inflammatory agents, but also antiviral substances.
Asunto(s)
Antivirales/farmacología , Lactobacillus plantarum , Polisacáridos Bacterianos/farmacología , Pyrus/microbiología , Animales , Antiinflamatorios/farmacología , Antivirales/aislamiento & purificación , Calicivirus Felino/efectos de los fármacos , Gatos , Perros , Hialuronoglucosaminidasa , Lactobacillales , Lactobacillus plantarum/clasificación , Células de Riñón Canino Madin Darby , Norovirus/efectos de los fármacos , Orthomyxoviridae/efectos de los fármacos , Polisacáridos Bacterianos/aislamiento & purificación , Especificidad de la EspecieRESUMEN
Carbohydrates play important and diverse roles in the fundamental processes of life. We have established a method for accurately and a large-scale synthesis of functional carbohydrates with diverse properties using a unique enzymatic method. Furthermore, various artificial glycan-conjugated molecules have been developed by adding these synthetic carbohydrates to macromolecules and to middle- and low-molecular-weight molecules with different properties. These glycan-conjugated molecules have biological activities comparable to or higher than those of natural compounds and present unique functions. In this review, several synthetic glycan-conjugated molecules are taken as examples to show design, synthesis, and function.
Asunto(s)
Antivirales/síntesis química , Factores Biológicos/síntesis química , Glicoconjugados/síntesis química , Polisacáridos/química , Sialoglicoproteínas/síntesis química , Animales , Antivirales/farmacología , Factores Biológicos/farmacología , Conformación de Carbohidratos , Quimioinformática/métodos , Reactivos de Enlaces Cruzados/química , Diseño de Fármacos , Glicoconjugados/farmacología , Glicósidos/química , Glicosilación , Humanos , Nanopartículas/química , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/crecimiento & desarrollo , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Sialoglicoproteínas/farmacologíaRESUMEN
The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3',4'-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.
Asunto(s)
Endonucleasas/antagonistas & inhibidores , Luteolina/síntesis química , Luteolina/farmacología , Orthomyxoviridae/efectos de los fármacos , Antivirales/síntesis química , Antivirales/farmacología , Dominio Catalítico/efectos de los fármacos , Proteínas Virales/antagonistas & inhibidoresRESUMEN
The growing resistance of the influenza virus to widely used competitive neuraminidase inhibitors occupying the active site of the enzyme requires the development of bifunctional compounds that can simultaneously interact with other regulatory sites on the protein surface. When developing such an inhibitor and combining structural fragments that could be located in the sialic acid cavity of the active site and the adjacent 430-cavity, it is necessary to select a suitable linker not only for connecting the fragments, but also to ensure effective interactions with the unique arginine triad Arg118-Arg292-Arg371 of neuraminidase. Using molecular modeling, we have demonstrated the usefulness of the sulfonamide group in the linker design and the potential advantage of this functional group over other isosteric analogues.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Neuraminidasa/metabolismo , Orthomyxoviridae/enzimología , Sulfonamidas/química , Antivirales/síntesis química , Antivirales/química , Dominio Catalítico , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Regulación Viral de la Expresión Génica/efectos de los fármacos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Orthomyxoviridae/efectos de los fármacos , Relación Estructura-Actividad , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteínas Virales/metabolismoRESUMEN
To date, the 'one bug-one drug' approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral infections that turn out to be pathogenic for humans. Evidently, there is an urgent need for new strategies to develop efficient antiviral agents with broad-spectrum activities. In this paper, we identified camphene derivatives that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses, including influenza virus A/PR/8/34 (H1N1), Ebola virus (EBOV), and the Hantaan virus. The lead-compound 2a, with pyrrolidine cycle in its structure, displayed antiviral activity against influenza virus (IC50 = 45.3 µM), Ebola pseudotype viruses (IC50 = 0.12 µM), and authentic EBOV (IC50 = 18.3 µM), as well as against pseudoviruses with Hantaan virus Gn-Gc glycoprotein (IC50 = 9.1 µM). The results of antiviral activity studies using pseudotype viruses and molecular modeling suggest that surface proteins of the viruses required for the fusion process between viral and cellular membranes are the likely target of compound 2a. The key structural fragments responsible for efficient binding are the bicyclic natural framework and the nitrogen atom. These data encourage us to conduct further investigations using bicyclic monoterpenoids as a scaffold for the rational design of membrane-fusion targeting inhibitors.