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Synthetic approaches and application of clinically approved small-molecule drugs to treat hepatitis.European Journal of Medicinal Chemistry Dec 2023Hepatitis, a global public health concern, presents a significant burden on healthcare systems worldwide. Particularly, hepatitis B and C are viral infections that can... (Review)
Review
Hepatitis, a global public health concern, presents a significant burden on healthcare systems worldwide. Particularly, hepatitis B and C are viral infections that can lead to severe liver damage, cirrhosis, and even hepatocellular carcinoma (HCC). The urgency to combat these diseases has driven researchers to explore existing small-molecule drugs as potential therapeutics. This comprehensive review provides a systematic overview of synthetic routes to key antiviral agents used to manage hepatitis. Furthermore, it elucidates the mechanisms of action of these drugs, shedding light on their interference with viral replication and liver disease progression. The review also discusses the clinical applications of these drugs, including their use in combination therapies and various patient populations. By evaluating the synthetic pathways and clinical utility of these drugs, this review not only consolidates current knowledge but also highlights potential future directions for research and drug development in the fight against hepatitis, ultimately contributing to improved patient outcomes and reduced global disease burden.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Antiviral Agents; Hepatitis B; Hepatitis B virus
PubMed: 37922830
DOI: 10.1016/j.ejmech.2023.115919 -
Scientific Reports Oct 2023The selection pressure imposed by the host immune system impacts hepatitis B virus (HBV) quasispecies variability. This study evaluates HBV genetic diversity in...
The selection pressure imposed by the host immune system impacts hepatitis B virus (HBV) quasispecies variability. This study evaluates HBV genetic diversity in different biological fluids. Twenty paired serum, oral fluid, and DBS samples from chronic HBV carriers were analyzed using both Sanger and next generation sequencing (NGS). The mean HBV viral load in serum was 5.19 ± 4.3 log IU/mL (median 5.29, IQR 3.01-7.93). Genotype distribution was: HBV/A1 55% (11/20), A2 15% (3/20), D3 10% (2/20), F2 15% (3/20), and F4 5% (1/20). Genotype agreement between serum and oral fluid was 100% (genetic distances 0.0-0.006), while that between serum and DBS was 80% (genetic distances 0.0-0.115). Two individuals presented discordant genotypes in serum and DBS. Minor population analysis revealed a mixed population. All samples displayed mutations in polymerase and/or surface genes. Major population analysis of the polymerase pointed to positions H122 and M129 as the most polymorphic (≥ 75% variability), followed by V163 (55%) and I253 (50%). Neither Sanger nor NGS detected any antiviral primary resistance mutations in the major populations. Minor population analysis, however, demonstrated the rtM204I resistance mutation in all individuals, ranging from 2.8 to 7.5% in serum, 2.5 to 6.3% in oral fluid, and 3.6 to 7.2% in DBS. This study demonstrated that different fluids can be used to assess HBV diversity, nonetheless, genotypic differences according to biological compartments can be observed.
Topics: Humans; Hepatitis B virus; Quasispecies; Hepatitis B, Chronic; Mutation; Genotype; DNA, Viral; Hepatitis B
PubMed: 37813888
DOI: 10.1038/s41598-023-43655-0 -
Bioorganic & Medicinal Chemistry Letters Aug 2023The protein that forms the inner shell of the HBV virus, known as the capsid core protein, plays a crucial role in allowing chronic HBV infections to persist. Studies...
The protein that forms the inner shell of the HBV virus, known as the capsid core protein, plays a crucial role in allowing chronic HBV infections to persist. Studies have shown that disrupting the assembly of the capsid can effectively combat the virus, and small molecule drugs that target the HBV capsid assembly modulator (CAM) process have been successful in clinical trials. Herein is described a distinct series of di-fluoro azepane CAMs with exceptional potency, pharmacokinetic, and solubility properties.
Topics: Capsid; Hepatitis B virus; Virus Assembly; Antiviral Agents; Capsid Proteins; Virus Replication
PubMed: 37247697
DOI: 10.1016/j.bmcl.2023.129350 -
Nucleic Acids Research Aug 2023Hepatitis B virus (HBV) is one of the most dangerous human pathogenic viruses found in all corners of the world. Recent sequencing of ancient HBV viruses revealed that...
Hepatitis B virus (HBV) is one of the most dangerous human pathogenic viruses found in all corners of the world. Recent sequencing of ancient HBV viruses revealed that these viruses have accompanied humanity for several millenia. As G-quadruplexes are considered to be potential therapeutic targets in virology, we examined G-quadruplex-forming sequences (PQS) in modern and ancient HBV genomes. Our analyses showed the presence of PQS in all 232 tested HBV genomes, with a total number of 1258 motifs and an average frequency of 1.69 PQS per kbp. Notably, the PQS with the highest G4Hunter score in the reference genome is the most highly conserved. Interestingly, the density of PQS motifs is lower in ancient HBV genomes than in their modern counterparts (1.5 and 1.9/kb, respectively). This modern frequency of 1.90 is very close to the PQS frequency of the human genome (1.93) using identical parameters. This indicates that the PQS content in HBV increased over time to become closer to the PQS frequency in the human genome. No statistically significant differences were found between PQS densities in HBV lineages found in different continents. These results, which constitute the first paleogenomics analysis of G4 propensity, are in agreement with our hypothesis that, for viruses causing chronic infections, their PQS frequencies tend to converge evolutionarily with those of their hosts, as a kind of 'genetic camouflage' to both hijack host cell transcriptional regulatory systems and to avoid recognition as foreign material.
Topics: Humans; G-Quadruplexes; Genome, Human; Genomics; Hepatitis B virus; Paleontology; Biological Evolution
PubMed: 37395407
DOI: 10.1093/nar/gkad556 -
Nature Communications Mar 2024Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na-taurocholate...
Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor's extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.
Topics: Humans; Hepatitis B virus; Antiviral Agents; Hepatitis B; Receptors, Virus; Bile Acids and Salts; Hepatitis Delta Virus; Symporters; Virus Internalization; Hepatocytes; Lipopeptides
PubMed: 38509088
DOI: 10.1038/s41467-024-46706-w -
Cell May 2024Hepatitis B virus (HBV) is a small double-stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two...
Hepatitis B virus (HBV) is a small double-stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two overlapping reading frames, and during evolution, multiple selective pressures can act on shared nucleotides. This study combines an RNA-based HBV cell culture system with deep mutational scanning (DMS) to uncouple cis- and trans-acting sequence requirements in the HBV genome. The results support a leaky ribosome scanning model for polymerase translation, provide a fitness map of the HBV polymerase at single-nucleotide resolution, and identify conserved prolines adjacent to the HBV polymerase termination codon that stall ribosomes. Further experiments indicated that stalled ribosomes tether the nascent polymerase to its template RNA, ensuring cis-preferential RNA packaging and reverse transcription of the HBV genome.
Topics: Humans; Genome, Viral; Hepatitis B virus; Mutation; Reverse Transcription; Ribosomes; RNA, Viral; Cell Line
PubMed: 38723628
DOI: 10.1016/j.cell.2024.04.008 -
ELife Aug 2023Prior to the COVID-19 pandemic, the World Health Organization named vaccine hesitancy as one of the top 10 threats to global health. The impact of hesitancy on the... (Review)
Review
Prior to the COVID-19 pandemic, the World Health Organization named vaccine hesitancy as one of the top 10 threats to global health. The impact of hesitancy on the uptake of human papillomavirus (HPV) vaccines was of particular concern, given the markedly lower uptake compared to other adolescent vaccines in some countries, notably the United States. With the recent approval of COVID-19 vaccines, coupled with the widespread use of social media, concerns regarding vaccine hesitancy have grown. However, the association between COVID-related vaccine hesitancy and cancer vaccines such as HPV is unclear. To examine the potential association, we performed two reviews using Ovid Medline and APA PsychInfo. Our aim was to answer two questions: (1) Is COVID-19 vaccine hesitancy, intention, or uptake associated with HPV or hepatitis B (HBV) vaccine hesitancy, intention, or uptake? and (2) Is exposure to COVID-19 vaccine misinformation on social media associated with HPV or HBV vaccine hesitancy, intention, or uptake? Our review identified few published empirical studies that addressed these questions. Our results highlight the urgent need for studies that can shift through the vast quantities of social media data to better understand the link between COVID-19 vaccine misinformation and disinformation and its impact on uptake of cancer vaccines.
Topics: Adolescent; Humans; Cancer Vaccines; COVID-19; COVID-19 Vaccines; Hepatitis B virus; Intention; Pandemics; Papillomavirus Infections; Social Media; Vaccination Hesitancy
PubMed: 37594016
DOI: 10.7554/eLife.85743 -
Hepatology Communications Nov 2023It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection....
BACKGROUND
It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape.
METHODS
We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance.
RESULTS
Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies.
CONCLUSIONS
HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.
Topics: Humans; Animals; Mice; Hepatitis B virus; Citrate (si)-Synthase; Macrophages; Immunity, Innate; Pyruvate Dehydrogenase Complex
PubMed: 37820280
DOI: 10.1097/HC9.0000000000000294 -
World Journal of Gastroenterology Feb 2024Approximately 12-72 million people worldwide are co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). This concurrent infection can lead to several...
Approximately 12-72 million people worldwide are co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). This concurrent infection can lead to several severe outcomes with hepatic disease, such as cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, being the most common. Over the past few decades, a correlation between viral hepatitis and autoimmune diseases has been reported. Furthermore, autoantibodies have been detected in the serum of patients co-infected with HBV/HDV, and autoimmune features have been reported. However, to date, very few cases of clinically significant autoimmune hepatitis (AIH) have been reported in patients with HDV infection, mainly in those who have received treatment with pegylated interferon. Interestingly, there are some patients with HBV infection and AIH in whom HDV infection is unearthed after receiving treatment with immunosuppressants. Consequently, several questions remain unanswered with the challenge to distinguish whether it is autoimmune or "autoimmune-like" hepatitis being the most crucial. Second, it remains uncertain whether autoimmunity is induced by HBV or delta virus. Finally, we investigated whether the cause of AIH lies in the previous treatment of HDV with pegylated interferon. These pressing issues should be elucidated to clarify whether new antiviral treatments for HDV, such as Bulevirtide or immu-nosuppressive drugs, are more appropriate for the management of patients with HDV and AIH.
Topics: Humans; Hepatitis Delta Virus; Hepatitis, Autoimmune; Hepatitis B; Hepatitis B virus; Interferons; Liver Neoplasms; Polyethylene Glycols; Antiviral Agents
PubMed: 38516234
DOI: 10.3748/wjg.v30.i8.799 -
Clinics in Liver Disease Nov 2023Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately... (Review)
Review
Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately effective interventions exist to decrease transmission. Counseling on the risk of maternal-to-child transmission, care pathways to decrease transmission, and the implications of HBV and HDV on pregnancy outcomes are the key components of caring for pregnant people living with HBV and HDV.
Topics: Infant; Pregnancy; Female; Humans; Hepatitis B virus; Hepatitis Delta Virus; Hepatitis B; Hepatitis B Surface Antigens; Infectious Disease Transmission, Vertical
PubMed: 37778777
DOI: 10.1016/j.cld.2023.05.007