Search Results (45)

Several natural products have been shown to display antiviral activity against the hepatitis B virus (HBV), among a number of other viruses. In a previous study, the hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest were tested on the hepatoma cell line HepG2.2.15, which constitutively produces HBV. One of the species that exerted inhibitory activity on HBV replication was Senna silvestris. The aim of this study was the bioassay-guided purification of the ethanol fraction of leaves of S. silvestris, which displayed the most significant inhibitory activity against HBV. After solvent extraction and two rounds of reverse-phase HPLC purification, NMR analysis identified salsolinol as the compound that may exert the desired antiviral activity. The purified compound exerted inhibition of both HBV DNA and core HBV DNA. Pure salsolinol obtained from a commercial source also displayed anti-HBV DNA inhibition, with an approximate MIC value of 12 µM. Although salsolinol is widely used in Chinese traditional medicine to treat congestive heart failure, it has also been associated with Parkinson’s disease. More studies are warranted to analyze the effect of changes in its chemical conformation, searching for potent antiviral, perhaps dual agents against HBV and HIV, with reduced toxicity. Full article

Hepatitis B virus (HBV) is a causative reagent that frequently causes progressive liver diseases, leading to the development of acute hepatitis, chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma. Despite several antiviral drugs, including interferon-α and nucleotide derivatives, being approved for clinical treatment of HBV, critical issues remain unresolved, e.g., their low-to-moderate efficacy and adverse side effects, as well as resistant strains. In this study, twenty-three matrine derivatives were synthesized, and their antiviral effects against HBV were evaluated. Of these, eleven compounds inhibited HBeAg secretion significantly more than the positive control, lamivudine (3TC). Among the compounds synthesized in this study, compounds 4a and 4d had the most potent inhibitory activity, with IC₅₀ value of 41.78 and 33.68 μM, respectively. Compounds 1h, 4a, and 4d were also subjected to molecular docking studies. These compounds inhibited viral gene expression and viral propagation in a cell culture model. Thus, we believe our compounds could serve as resource for antiviral drug development. Full article

Background: Hepatitis D virus (HDV) is a defective virus requiring co-infection with hepatitis B virus (HBV) to replicate, occurring in 5% of HBV+ patients. Bulevirtide (BLV) is now the first-in-class specific anti-HDV agent, inhibiting HDV binding to NTCP, with good tolerability and good virological and biochemical response rates. Currently, little is known about its pharmacokinetic/pharmacodynamic (PK/PD), as well as potential drug-drug interaction (DDI) profile. In this work we provide a systematic review of the current knowledge on these aspects. Methods: A literature review of PK, PD and DDI profiles of BLV was conducted from Pubmed and EMA websites. Experimentally tested interactions and hypothetical mechanisms of interaction were evaluated, mostly focusing on usually co-administered anti-infective agents and other drugs interacting on NTCP. Results: BLV shows non-linear PK, due to target-mediated drug disposition, so its PK as well as PD is expected to be influenced by interactions of other drugs with NTCP, while it is not substrate of CYPs and ABC transporters. In-vivo investigated DDIs showed no clinically relevant interactions, but a weak inhibitory effect was suggested on CYP3A4 in a work when used at high doses (10 mg instead of 2 mg). In vitro, a weak inhibitory effect on OATP transporters was observed, but at much higher concentrations than the ones expected in vivo. Conclusions: The drug-drug interaction potential of BLV can be considered generally very low, particularly at the currently approved dose of 2 mg/day. Some attention should be paid to the coadministration of drugs with known binding and/or inhibition of NTCP. Full article

Honeybee venom (HBV) is a complex mixture of proteins and enzymes used in traditional medicine to treat various ailments. HBV has multiple pharmacological effects, making it a promising therapeutic agent in several medical areas. In addition, HBV has many potential cosmetic applications as an anti-aging agent and for the treatment of various skin conditions. HBV’s antioxidant properties are also of great interest, as oxidative stress contributes to the onset and progression of many diseases. Several attempts have been made to assess HBV’s antioxidant activity, mainly using the DPPH assay. However, variability in experimental protocols and the lack of experimental details make the interpretation of results difficult. In this study, we aim to address the source of this variability by investigating the antioxidant activity of HBV in a detergent-based buffer across a range of pH values (from 3 to 7.5). We also analyze the contribution of melittin, the major component of HBV. Our results demonstrate that the DPPH radical scavenging activity of HBV is strongly influenced by the solvent used and by pH. Specifically, we show, for the first time, that HBV exhibits antioxidant activity under mildly acidic conditions, following a complex fast + slow reaction pattern. Interestingly, melittin contributes only partially to the total antioxidant activity of HBV. Overall, this work provides new insights into the antioxidant properties of HBV. Full article

Rubella Virus, Cytomegalovirus (CMV), Herpes Simplex Virus-2 (HSV-2), Hepatitis B (HBV) and Hepatitis C virus (HCV) can cause serious fetal disease. The seropositivity rates of these agents vary among countries and geographic regions. This study aimed to analyze the prevalence rates and diagnostic methods used in studies investigating the seroprevalence of viral pathogens in the TORCH group among pregnant women in Turkey between 2005 and 2024. A systematic search was conducted using electronic databases between January 2005 and January 2024. A total of 60 studies meeting the inclusion criteria were included. Data quality control was assessed using the Joanna Briggs Institute guideline prevalence studies checklist. Heterogeneity was measured using the I-squared (I²) statistic in the Comprehensive Meta Analysis (CMA) program. The average seropositivity rates for Rubella, CMV, HSV-2, HBV and HCV in Turkey were determined as 91.18%, 94.81%, 35.52%, 1.66% and 0.25%, respectively. When the diagnostic methods were examined, it was determined that ELISA and ECLIA methods were used most frequently. The seropositivity of the agents did not show statistically significant differences according to the year periods, geographical regions and age of the patients (p > 0.05). The highest prevalence rates of Rubella and HSV-2 in pregnant women were reported in the Mediterranean region, the highest prevalence rates of CMV and HCV in the Southeastern Anatolia region and the highest seroprevalence of Anti HBs in the Marmara region. The results of this study support the necessity of increasing public awareness in the control of fetal infection caused by TORCH viral agents, prenatal screening, vaccination for Rubella and HBV and compliance with hygiene conditions for agents such as CMV, HSV-2 and HCV. The results of this study highlight the need to increase public awareness on prenatal screening for the control of fetal infection caused by all TORCH viral agents, vaccination for Rubella and HBV and compliance with hygiene conditions for agents such as CMV, HSV-2 and HCV. Full article

Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg²⁺ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC₅₀ values in the low μM range (1.1–7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure–activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents. Full article

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission. Full article

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrio^R. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent. Full article

Chronic infection with hepatitis B virus (HBV) develops in millions of patients per year, despite the availability of effective prophylactic vaccines. Patients who resolve acute HBV infection develop HBV-specific polyfunctional T cells accompanied by neutralizing antibodies, while in patients with chronic hepatitis B (CHB), immune cells are dysfunctional and impaired. We describe a lipid nanoparticle (LNP)-formulated mRNA vaccine, optimized for the expression of HBV core, polymerase, and surface (preS2-S) antigens with the aim of inducing an effective immune response in patients with CHB. Prime and prime/boost vaccination with LNP-formulated mRNA encoding for core, pol, and/or preS2-S dosing strategies were compared in naive C57BL/6 and BALB/c mice. Immune responses were assessed by IFN-γ ELISpot, intracellular cytokine staining (ICS), and ELISA for antibody production, whereas anti-viral efficacy was evaluated in the AAV-HBV mouse model. The mRNA vaccine induced strong antigen-specific polyfunctional T cell responses in these mouse models, accompanied by the emergence of anti-HBs and anti-HBe antibodies. After three immunizations, the antigen-specific immune stimulation resulted in up to 1.7 log₁₀ IU/mL reduction in systemic HBV surface antigen (HBsAg), accompanied by a transient drop in systemic HBeAg, and this was observed in 50% of the AAV-HBV-transduced mice in the absence of additional modalities such as adjuvants, HBsAg reducing agents, or checkpoint inhibitors. However, no treatment-related effect on viremia was observed in the liver. These results warrant further optimization and evaluation of this mRNA vaccine as a candidate in a multimodal therapeutic regimen for the treatment of chronic HBV infection. Full article

Hepatitis B virus (HBV) reactivation in the setting of immunosuppressive therapy is an increasingly recognized and preventable cause of elevated liver enzymes and clinical hepatitis in treated patients. However, not all immunosuppressive therapies confer the same risk. The purpose of this article was to review the literature on risks of HBV reactivation associated with immunosuppressive agents and propose a management algorithm. We searched Google Scholar, PubMed, and MEDLINE for studies related to hepatitis B reactivation and various immunosuppressive agents. The risk of HBV reactivation was found to differ by agent and depending on whether a patient had chronic HBV (HBsAg+) or past HBV (HBsAg−, anti-HBc+). The highest risk of reactivation (>10%) was associated with anti-CD20 agents and hematopoietic stem cell transplants. Multiple societies recommend HBV-specific anti-viral prophylaxis for patients with positive HBsAg prior to the initiation of immunosuppressive therapy, while the guidance for HBsAg− patients is more variable. Clinicians should check HBV status prior to beginning an immune-suppressive therapy. Patients with positive HBsAg should be initiated on antiviral prophylaxis in the majority of cases, whereas HBsAg− individuals should be evaluated on a case-by-case basis. Further research is required to determine the optimum duration of therapy. Full article

Hepatitis B virus (HBV) infection is a worldwide medical issue with significant morbidity and mortality, as it is the main cause of chronic liver disease and hepatocellular carcinoma (HCC). Both innate and adaptive immune responses play a key role in HBV replication and suppression. Recently, the pathophysiological function of interleukins (IL) in the natural course of HBV has gained much attention as a result of the broad use of anti-interleukin agents for a variety of autoimmune diseases and the accompanying risk of HBV reactivation. We present a narrative review regarding the role of IL in HBV infection. Collectively, the pro-inflammatory ILs, namely IL-1, IL-5, IL-6, IL-12 and IL-21, seem to play a critical role in the suppression of HBV replication. In contrast, the anti-inflammatory cytokines IL-10, IL-23 and IL-35 probably act as HBV replication enhancers, while IL-17 has been correlated with HBV-related liver injury. Interestingly enough, IL-2, IL-4 and IL-12 have been tried as therapeutic options against HBV infection with contradictory results. Lastly, the role of IL-22 remains largely ill defined, although preliminary data suggest that it may play a significant role in HBV replication, proliferation and subsequent liver damage. Full article

There has been over half a century since the discovery of hepatitis B virus (HBV) to now, but approximately 300 million patients with chronic hepatitis B (CHB) still live in the world, resulting in about one million deaths every year. Although currently approved antivirals (e.g., nucleoside analogues) are effective at reducing HBV replication, they have almost no impact on the existing HBV covalently closed circular DNA (cccDNA) reservoir. HBV cccDNA is a critical obstacle to the complete elimination of the virus via antiviral therapy. The true cure of HBV infection requires the eradication of viral cccDNA from HBV-infected cells; thus, the development of new agents directly or indirectly targeting HBV cccDNA is urgently needed due to the limitations of current available drugs against HBV infection. In this regard, it is the major focus of current anti-HBV research worldwide via different mechanisms to either inactivate/inhibit (functional cure) or eliminate (complete cure) HBV cccDNA. Therefore, this review discussed and summarized recent advances and challenges in efforts to inactivate/silence or eliminate viral cccDNA using anti-HBV agents from different sources, such as small molecules (including epigenetic drugs) and polypeptides/proteins, and siRNA or gene-editing approaches targeting/attenuating HBV cccDNA via different mechanisms, as well as future directions that may be considered in efforts to truly cure chronic HBV infection. In conclusion, no breakthrough has been made yet in attenuating HBV cccDNA, although a number of candidates have advanced into the phase of clinical trials. Furthermore, the overwhelming majority of the candidates function to indirectly target HBV cccDNA. No outstanding candidate directly targets HBV cccDNA. Relatively speaking, CCC_R08 and nitazoxanide may be some of the most promising agents to clear HBV infection in small molecule compounds. Additionally, CRISPR-Cas9 systems can directly target HBV cccDNA for decay and demonstrate significant anti-HBV activity. Consequently, gene-editing approaches targeting HBV cccDNA may be one of the most promising means to achieve the core goal of anti-HBV therapeutic strategies. In short, more basic studies on HBV infection need to be carried out to overcome these challenges. Full article

The Hepatitis B virus (HBV) HBx and HBc proteins play a crucial role in associating with covalently closed circular DNA (cccDNA), the primary factor contributing to intrahepatic viral persistence and a major obstacle in achieving a cure for HBV. The cccDNA serves as a reservoir for viral persistence. Targeting the viral HBc and HBx proteins’ interaction with cccDNA could potentially limit HBV replication. In this study, we present epitopes identified from global consensus sequences of HBx and HBc proteins that have the potential to serve as targets for the development of effective vaccine candidates. Furthermore, conserved residues identified through this analysis can be utilized in designing novel, site-specific anti-HBV agents capable of targeting all major genotypes of HBV. Our approach involved designing global consensus sequences for HBx and HBc proteins, enabling the analysis of variable regions and highly conserved motifs. These identified motifs and regions offer potent sites for the development of peptide vaccines, the design of site-specific RNA interference, and the creation of anti-HBV inhibitors. The epitopes derived from global consensus sequences of HBx and HBc proteins emerge as promising targets for the development of effective vaccine candidates. Additionally, the conserved residues identified provide valuable insights for the development of innovative, site-specific anti-HBV agents capable of targeting all major genotypes of HBV from A to J. Full article

Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increased the accumulation of cytoplasmic empty capsids, presumably by targeting the hydrophobic pocket at the dimer-dimer interface of HBV core protein (HBc). Canocapavir treatment markedly reduced the egress of naked capsids, which could be reversed by Alix overexpression through a mechanism other than direct association of Alix with HBc. Moreover, Canocapavir interfered with the interaction between HBc and HBV large surface protein, resulting in diminished production of empty virions. Of particular note, Canocapavir induced a conformational change of capsids, with the C-terminus of HBc linker region fully exposed on the exterior of capsids. We posit that the allosteric effect may have great importance in the anti-HBV activity of Canocapavir, given the emerging virological significance of HBc linker region. In support of this notion, the mutation at HBc V124W typically recapitulated the conformational change of the empty capsid with aberrant cytoplasmic accumulation. Collectively, our results indicate Canocapavir as a mechanistically distinct type of CpAMs against HBV infection. Full article

We investigate the role of Tachyplesin (Tpl), a marine antimicrobial cell-penetrating peptide, as an anti-HBV agent. Our findings, using confocal microscopy and flow cytometry, demonstrate the internalization of FITC-Tpl in both Huh7 and HepG2 cell lines. Further, our results show that Tpl inhibits the expression of HBV proteins, including hepatitis B surface antigen (HBsAg) and hepatitis B ‘e’ antigen (HBeAg) in cell supernatants of human liver cell lines transfected with 1.3× pHBV. Interestingly Tpl also reduces levels of HBV pre-core RNA and HBV pregenomic RNA, suggesting that Tpl-mediated inhibition occurs at the early stages of HBV replication, including viral transcription. In addition, Tpl led to a significant reduction in levels of hepatitis B virion secretion. In sum, here we demonstrate the potent anti-HBV activity of Tpl at non-cytotoxic concentrations indicating the potential of Tpl to emerge as an effective therapeutic peptide against HBV. Full article