RESUMO
The hepatitis B virus (HBV) is a global public health challenge due to its highly contagious nature. It is estimated that almost 300 million people live with chronic HBV infection annually. Although nucleoside analogs markedly reduce the risk of liver disease progression, the analogs do not fully eradicate the virus. As such, new treatment options and drugs are urgently needed. Psoralen is a nourishing monomer of Chinese herb and is known to inhibit virus replication and inactivate viruses. In this study, we evaluated the potential of psoralen as an anti-HBV agent. Quantitative PCR and Southern blot analysis revealed that psoralen inhibited HBV replication in HepG2.2.15 âcells in a concentration-dependent manner. Moreover, psoralen was also active against the 3TC/ETV-dual-resistant HBV mutant. Further investigations revealed that psoralen suppressed both HBV RNA transcription and core protein expression. The transcription factor FOXO1, a known target for PGC1α co-activation, binds to HBV pre-core/core promoter enhancer II region and activates HBV RNA transcription. Co-immunoprecipitation showed that psoralen suppressed the expression of FOXO1, thereby decreasing the binding of FOXO1 co-activator PGC1α to the HBV promoter. Overall, our results demonstrate that psoralen suppresses HBV RNA transcription by down-regulating the expression of FOXO1 resulting in a reduction of HBV replication.
Assuntos
Ficusina , Hepatite B , Replicação Viral , Antivirais/farmacologia , Ficusina/farmacologia , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Humanos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Regiões Promotoras Genéticas , RNA Viral , Transcrição Gênica , Replicação Viral/efeitos dos fármacosRESUMO
To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC50 = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Reposicionamento de Medicamentos , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Linhagem Celular , Aprovação de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacosRESUMO
HBV capsid assembly has been viewed as an attractive target for new antiviral therapies against HBV. On the basis of a lead compound 4r, we further investigated this target to identify novel active compounds with appropriate anti-HBV potencies and improved pharmacokinetic (PK) properties. Structure-activity relationship studies based on metabolic pathways of 4r led to the identification of a phthalazinone derivative 19f with appropriate anti-HBV potencies (IC50 = 0.014 ± 0.004 µM in vitro), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of 19f resulted in a 2.67 log reduction of the HBV DNA viral load during a 4-week treatment with 150 mg/kg dosing twice daily.
Assuntos
Antivirais/química , Capsídeo/efeitos dos fármacos , Descoberta de Drogas/métodos , Vírus da Hepatite B/efeitos dos fármacos , Ftalazinas/química , Animais , Antivirais/farmacologia , Capsídeo/fisiologia , Cães , Haplorrinos , Células Hep G2 , Vírus da Hepatite B/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ftalazinas/farmacologia , RatosRESUMO
Since the outbreak of novel coronavirus pneumonia (COVID-19) in December 2019, more than 2,500,000 people worldwide have been diagnosed with SARS-CoV-2 as of April 22. In response to this epidemic, China has issued seven trial versions of diagnosis and treatment protocol for COVID-19. According to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional Chinese medicine, which have been reported with good clinical treatment effects. Moreover, with further understanding of SARS-CoV-2 virus, new drugs targeting specific SARS-CoV-2 viral components arise and investigations on these novel anti-SARS-CoV-2 agents are also reviewed.
Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Medicina Tradicional Chinesa/métodos , Pandemias , Pneumonia Viral , Betacoronavirus/fisiologia , COVID-19 , Protocolos Clínicos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etiologia , Pneumonia Viral/fisiopatologia , SARS-CoV-2RESUMO
A palladium-catalyzed asymmetric synthesis of planar chiral metallocene compounds is reported. The reaction stereoselectively functionalized one of the ortho C-H bonds of Cp rings by intramolecular cyclization to form indenone derivatives in high yields with excellent enantioselectivity. The mild set of reaction conditions allowed a wide variety of chiral metallocene compounds to be synthesized with broad functional group tolerance. The influences of preinstalled chiralities on the other Cp-ring were also investigated.
RESUMO
A palladium-catalyzed Heck-type cascade reaction of aryl halides and N-tosyl hydrazones is reported. The neopentylpalladium species, generated from an intramolecular Heck-type insertion reaction of aryl halides, could efficiently react with carbenes to form highly functionalized alkenes. The synthesis of spiro compounds was also explored via a multiple Heck-type insertion reaction with N-tosyl hydrazone.
RESUMO
A Pd-catalyzed chemoselective Catellani reaction of iodopyrroles was developed. The rare chemoselectivity between two different aryl halides was realized by optimizing the kinetics of the different steps of this multicomponent process. The new developed method led to the rapid synthesis of rhazinal in a highly efficient manner.