RESUMO
Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor.
Assuntos
Antivirais , Vírus da Hepatite B , Transportadores de Ânions Orgânicos Dependentes de Sódio , Triterpenos Pentacíclicos , Simportadores , Internalização do Vírus , Humanos , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Simportadores/antagonistas & inibidores , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Internalização do Vírus/efeitos dos fármacos , Células Hep G2 , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/síntese química , Antígenos de Superfície da Hepatite B/metabolismoRESUMO
This study examined the elimination of sulfonamide antibiotics (SAs) by constructed wetland substrates with NaOH-modified corn straw biochar and assessed the impact of environmental conditions on the effectiveness of SAs removal. The study demonstrated that the constructed wetland substrate with NaOH-modified biochar significantly eliminated eight SAs, with a removal rate of over 94â¯%. During the removal process, the intermediates will undergo regeneration of the parent compounds under low DO concentrations. This was based on the linear stepwise regression analysis and Geodetector models. The results showed that SA types COD, NH4+-N, TN, and DO had a stronger influence. The dominant bacteria in the constructed wetland system were mainly affected by antibiotic concentration, DO, NH4+-N and NO3--N, which affected the removal of antibiotics. Overall, the constructed wetland substrate with NaOH-modified corn straw biochar can be effectively employed as an ecological method for eliminating SAs from the environment.