Depsides: lichen metabolites active against hepatitis C virus.
Ontology highlight
ABSTRACT:
SUBMITTER: Vu TH
PROVIDER: S-EPMC4368788 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UNLABELLED:Certain nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more-potent agents that offer profound viral suppression. Here, we report that 4'-C-cyano-2-amino-2'-deoxyadenosine (CAdA) is a novel, highly potent inhibitor of both HBV (half maximal inhibitory concentration [IC50 ]?=?0.4 nM) and HIV-1 (IC50 ?=?0.4 nM). In contrast, the approved anti-HBV NRTI, entecavir (ETV), potently inhibits HBV (IC50 ?=?0.7 nM), but is much less active against HIV-1 (IC50 ?=?1,000 nM). Similarly, the highly potent HIV-1 inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA; IC50 ?=?0.3 nM) is less active against HBV (IC50 ?=?160 nM). Southern analysis using Huh-7 cells transfected with HBV-containing plasmids demonstrated that CAdA was potent against both wild-type (IC50 ?=?7.2 nM) and ETV-resistant HBV (IC50 ?=?69.6 nM for HBVETV-RL180M/S202G/M204V), whereas ETV failed to reduce HBVETV-RL180M/S202G/M204V DNA even at 1 ?M. Once-daily peroral administration of CAdA reduced HBVETV-RL180M/S202G/M204V viremia (P?=?0.0005) in human-liver-chimeric/ HBVETV-RL180M/S202G/M204V-infected mice, whereas ETV completely failed to reduce HBVETV-RL180M/S202G/M204V viremia. None of the mice had significant drug-related body-weight or serum human-albumin concentration changes. Molecular modeling suggests that a shallower HBV-RT hydrophobic pocket at the polymerase active site can better accommodate the slightly shorter 4'-cyano of CAdA-triphosphate (TP), but not the longer 4'-ethynyl of EFdA-TP. In contrast, the deeper HIV-1-RT pocket can efficiently accommodate the 4'-substitutions of both NRTIs. The ETV-TP's cyclopentyl ring can bind more efficiently at the shallow HBV-RT binding pocket. CONCLUSION:These data provide insights on the structural and functional associations of HBV- and HIV-1-RTs and show that CAdA may offer new therapeutic options for HBV patients.
| S-EPMC4589464 | biostudies-literature
Project description:Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
| S-EPMC4119598 | biostudies-literature
Project description:The lichen is a microbial consortium that mainly consists of fungi and either algae (Viridiplantae) or cyanobacteria. This structure also contains other bacteria, fungi, and viruses. However, RNA virus diversity associated with lichens is still unknown. Here, we analyzed RNA virus diversity in a lichen dominated by fungi and algae using dsRNA-seq technology and revealed that partitiviruses were dominant and active in the microbial consortium. The Partitiviridae sequences found in this study were classified into two genera, which have both plant- and fungi-infecting partitiviruses. This observation suggests that the lichen provides an opportunity for horizontal transfer of these partitiviruses among microbes that form the lichen consortium.
| S-EPMC7609399 | biostudies-literature
Project description:Virus-like particles (VLPs) can be efficiently produced by heterologous expression of viral structural proteins in yeast. Due to their repetitive structure, VLPs are extensively used for protein engineering and generation of chimeric VLPs with inserted foreign epitopes. Hamster polyomavirus VP1 represents a promising epitope carrier. However, insertion of large sized protein sequences may interfere with its self-assembly competence. The co-expression of polyomavirus capsid protein VP1 with minor capsid protein VP2 or its fusion protein may result in pseudotype VLPs where an intact VP1 protein mediates VLP formation. In the current study, the capacity of VP1 protein to self-assemble to VLPs and interact with the modified VP2 protein has been exploited to generate pseudotype VLPs displaying large-sized antibody molecules.Polyomavirus-derived pseudotype VLPs harbouring a surface-exposed functionally active neutralizing antibody specific to hepatitis B virus (HBV) surface antigen (HBsAg) have been generated. The pseudotype VLPs consisting of an intact hamster polyomavirus (HaPyV) major capsid protein VP1 and minor capsid protein VP2 fused with the anti-HBsAg molecule were efficiently produced in yeast Saccharomyces cerevisiae and purified by density-gradient centrifugation. Formation of VLPs was confirmed by electron microscopy. Two types of pseudotype VLPs were generated harbouring either the single-chain fragment variable (scFv) or Fc-engineered scFv on the VLP surface. The antigen-binding activity of the purified pseudotype VLPs was evaluated by ELISA and virus-neutralization assay on HBV-susceptible primary hepatocytes from Tupaia belangeri. Both types of the pseudotype VLPs were functionally active and showed a potent HBV-neutralizing activity comparable to that of the parental monoclonal antibody. The VP2-fused scFv molecules were incorporated into the VLPs with higher efficiency as compared to the VP2-fused Fc-scFv. However, the pseudotype VLPs with displayed VP2-fused Fc-scFv molecule showed higher antigen-binding activity and HBV-neutralizing capacity that might be explained by a better accessibility of the Fc-engineered scFv of the VLP surface.Polyomavirus-derived pseudotype VLPs harbouring multiple functionally active antibody molecules with virus-neutralizing capability may represent a novel platform for developing therapeutic tools with a potential application for post-exposure or therapeutic treatment of viral infections.
| S-EPMC4570255 | biostudies-literature
Project description:Ribonucleoside analog inhibitors (rNAI) target the hepatitis C virus (HCV) RNA-dependent RNA polymerase nonstructural protein 5B (NS5B) and cause RNA chain termination. Here, we expand our studies on β-d-2'-C-methyl-2,6-diaminopurine-ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2'-C-methyl-GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2'-C-methyl-DAPN-TP, behaves as an adenosine base analog. In vitro assays suggest that both metabolites are inhibitors of NS5B-mediated RNA polymerization. Additional factors, such as rNAI-TP incorporation efficiencies, intracellular rNAI-TP levels, and competition with natural ribonucleotides, were examined in order to further characterize the potential role of each nucleotide metabolite in vivo Finally, we found that although both 2'-C-methyl-GTP and 2'-C-methyl-DAPN-TP were weak substrates for human mitochondrial RNA (mtRNA) polymerase (POLRMT) in vitro, DAPN-PD1 did not cause off-target inhibition of mtRNA transcription in Huh-7 cells. In contrast, administration of BMS-986094, which also generates 2'-C-methyl-GTP and previously has been associated with toxicity in humans, caused detectable inhibition of mtRNA transcription. Metabolism of BMS-986094 in Huh-7 cells leads to 87-fold higher levels of intracellular 2'-C-methyl-GTP than DAPN-PD1. Collectively, our data characterize DAPN-PD1 as a novel and potent antiviral agent that combines the delivery of two active metabolites.
| S-EPMC4958185 | biostudies-literature
Project description:A systematic review of literature data on the antifungal potential of extracted lichen compounds and individual secondary metabolites against mold species of the genus Aspergillus is provided. Crude extracts from 49 epiphytic, 16 epigeic and 22 epilithic species of lichens and 44 secondary metabolites against 10 species, Aspergillus candidus, A. flavus, A. fumigatus, A. nidulans, A. niger, A. ochraceus, A. parasiticus, A. restrictus, A. stellatus and A. ustus, were analysed. Several measuring techniques were employed for such analyses. Lichen substances were extracted with alcoholic and other organic solvents mainly using the Soxhlet apparatus. Among the three most-studied mold species, the results showed that the crude extracts from the thalli of the lichens Cladonia foliacea, Hypotrachyna cirrhata, Leucodermia leucomelos, Platismatia glauca and Pseudevernia furfuracea against Aspergillus flavus, from C. foliacea, Nephroma arcticum and Parmelia sulcata against A. fumigatus and from Evernia prunastri, Hypogymnia physodes, Umbilicaria cylindrica and Variospora dolomiticola against A. niger have the greatest antifungal potential. The lichen secondary metabolites showed a higher inhibitory potential, e.g. protolichesterinic acid against A. flavus, lecanoric acid against A. fumigatus and orsellinic acid against A. niger; the other seven species of Aspergillus have been poorly studied and require further investigation. A comparison of the inhibitory potential of the tested mixtures of lichen substances and their secondary metabolites shows that they can compete with commonly used antifungal substances, such as ketoconazole and clotrimazole against A. flavus, A. nidulans, A. niger and A. parasiticus and fluconazole in the case of A. fumigatus.
| S-EPMC8716355 | biostudies-literature
Project description:Chronic hepatitis B virus (HBV) infection poses a significant health challenge due to associated morbidity and mortality from cirrhosis and hepatocellular cancer that eventually results in the breakdown of liver functionality. Nanotechnology has the potential to play a pivotal role in reducing viral load levels and drug-resistant HBV through drug targeting, thus reducing the rate of evolution of the disease. Apart from tissue targeting, intracellular delivery of a wide range of drugs is necessary to exert a therapeutic action in the affected organelles. This review encompasses the strategies and techniques that have been utilized to target the HBV-infected nuclei in liver hepatocytes, with a significant look at the new insights and most recent advances in drug carriers and their role in anti-HBV therapy.
| S-EPMC5977260 | biostudies-other
Project description:We used whole genome expression profiling to analyze the effects of Hepatitis E Virus (HEV) on the mRNA transcriptome of A549/D3 cells - particularly to identify differentially expressed genes which are associated with cholesterol metabolism.
2021-02-12 | GSE157820 | GEO
Project description:No vaccine against the hepatitis E virus (HEV) is currently licensed in Europe. In contrast, HEV-239 (Hecolin®, Xiamen Innovax Biotech Co., Xiamen, China), a vaccine against HEV genotype 4, has been available in China for 10 years. Challenges for the development of vaccines arise mainly from the differences between the genotypes with regard to distribution, transmission routes and risk groups. Other obstacles include the envelopment of HEV in blood by host membranes, replication in various organs outside the liver and weaker immune responses in vulnerable groups. This article reviews the current status of vaccines against HEV that are available and in advanced preclinical evaluation, with a focus on vaccine development strategies. Challenges and limitations are described.Current vaccine candidates focus on protein-based immunisation with the aim of inducing protective, neutralising antibody responses. The goal of the HEV-239 pivotal trial with more than 100,000 study participants was to prevent acute symptomatic infections. However, it is unclear to what extent asymptomatic infections were prevented by the vaccine and whether it is effective enough in patients at risk for a complicated course, such as patients with liver cirrhosis, immunosuppressed individuals and pregnant women. Efficient in vitro models are increasingly enabling the development of monoclonal neutralising antibodies for passive immunisation or therapy.Future vaccines should demonstrate clear protection against all genotypes in addition to a very good safety profile. The development of an efficient passive immunisation strategy, especially for immunosuppressed individuals, is desirable.
| S-EPMC8802100 | biostudies-literature
Project description:Hepatitis C virus (HCV)-infected patients undergoing liver transplantation universally experience rapid reinfection of their new liver graft. Current treatment protocols do not prevent graft reinfection and, in addition, an accelerated disease progression is observed. In the present study, we have evaluated a novel strategy to prevent HCV infection using a lectin, griffithsin (GRFT) that specifically binds N-linked high-mannose oligosaccharides that are present on the viral envelope. The antiviral effect of GRFT was evaluated in vitro using the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems. We show here that preincubation of HCVpp and HCVcc with GRFT prevents infection of Huh-7 hepatoma cells. Furthermore, GRFT interferes with direct cell-to-cell transmission of HCV. GRFT acts at an early phase of the viral life cycle by interfering in a genotype-independent fashion with the interaction between the viral envelope proteins and the viral receptor CD81. The capacity of GRFT to prevent infection in vivo was evaluated using uPA(+/+)-SCID mice (uPA stands for urokinase-type plasminogen activator) that harbor human primary hepatocytes in their liver (chimeric mice). In this proof-of-concept trial, we demonstrated that GRFT can mitigate HCV infection of chimeric mice. Treated animals that did become infected demonstrated a considerable delay in the kinetics of the viral infection. Our data demonstrate that GRFT can prevent HCV infection in vitro and mitigate HCV infection in vivo. GRFT treatment of chronically infected HCV patients undergoing liver transplantation may be a suitable strategy to prevent infection of the liver allograft.
| S-EPMC3194994 | biostudies-literature