OBJECTIVETo study the inhibitory activities of 3-O-β-chacotriosyl benzyl ursolate and its derivatives as potential new anti-influenza virus agents against the entry of H5N1 influenza viruses into the target cells.

METHODSFour target compounds were designed and synthesized, which were structurally related to the lead compound 3-O-β-chacotriosyl methyl ursolate (1). The inhibitory activities of these compounds were tested at a cellular level psuedovirus system targeting H5N1 influenza viruse entry.

RESULTS AND CONCLUSIONThe compounds 1b, 1c and 1d showed potent inhibitory activities against the entry of A/Thailand/Kan353/2004 pseudovirus into the target cells, and among them compound 1d showed the strongest inhibitory activity with an IC50 value of 0.96 ± 0.10 µmol/L. The structure-activity relationship analysis of these compounds indicated that when 17-COOH of ursolic acid was esterified, introduction of Me groups rather than aryl groups more strongly enhanced the inhibitory activity. Changing 17-COOH of ursolic acid into amide could increase the antiviral activity and decrease the cytotoxicity of the compounds in MDCK cells.

Animals ; Antiviral Agents ; chemistry ; Dogs ; Influenza A Virus, H5N1 Subtype ; drug effects ; physiology ; Madin Darby Canine Kidney Cells ; Structure-Activity Relationship ; Triterpenes ; chemistry ; Virus Internalization ; drug effects

Middle East respiratory syndrome (MERS) has raised global public health concerns. The recent outbreak of MERS coronavirus (MERS-CoV) infection has led to 1 338 laboratory-confirmed cases in 26 countries worldwide as reported till 19 June, 2015. MERS-CoV may be considered a zoonotic virus that has crossed the species barrier to humans, but the pathogenesis and the routes of transmission are not completely understood. Most MERS-CoV cases reported thus far have a history of residence in or travel to the Middle East. Human-to-human transmission though was observed on some occasions in Korea, it is documented as non-sustainable event. The envelope spike glycoprotein on the surface of MERS-CoV which mediates receptor binding, membrane fusion and viral entry is thought to be involved in the mechanism of MERS-CoV.No specific and effective treatment for MERS-CoV is currently recommended, although supportive treatment has played an important role. Prophylactic strategies are necessary to prevent MERS-CoV infection.
Coronavirus Infections ; diagnosis ; epidemiology ; therapy ; Humans ; Middle East Respiratory Syndrome Coronavirus ; pathogenicity ; physiology ; Spike Glycoprotein, Coronavirus ; metabolism ; Virus Internalization

Hepatitis c virus (HCV) infection has become one of the global public health problem,while there is no vaccine to prevent HCV infection, the so-called "cocktail" therapy that use a combination of drugs targeting multiple steps in the HCV infection cycle could achieve better curative effect. the process of HCV entering into host cell is the important step of drug intervention, in which HCV envelope protein El and E2, Host cell factors including Heparan sulfate(HS), CD81, scavenger receptor class B type I (SR-BI), Occludin (OCLD), Claudin (CLDN), low densitity lipoprotein receptor (LDLR), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), Liver/lymph node specific ICAM-3-grabbing integrin(L-SIGN), trans- ferrin receptor 1 (TfR1) and so on play a important role. The virus and the host factors can be used as targets of hcv entry inhibitors many studies have shown that as novel and promising compounds, HCV entry inhibitors combinating with other drugs can be more effective in the treatment of HCV, this paper have re- viewed targets and inhibitors of HCV enterring into host cell since 1990s.
Animals ; Antiviral Agents ; pharmacology ; Hepacivirus ; drug effects ; physiology ; Hepatitis C ; genetics ; metabolism ; virology ; Humans ; Receptors, Virus ; genetics ; metabolism ; Viral Envelope Proteins ; genetics ; metabolism ; Virus Internalization ; drug effects

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection.
Animals ; Carboxypeptidases/genetics/*metabolism ; Gene Products, pol/genetics/metabolism ; Heparan Sulfate Proteoglycans/metabolism ; Hepatitis B virus/*physiology ; Hepatocytes/metabolism/virology ; Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors/genetics/metabolism ; RNA Interference ; Symporters/antagonists & inhibitors/genetics/metabolism ; Viral Envelope Proteins/metabolism ; Virus Internalization

This study was designed to discover filovirus entry inhibitors in a drug library of commercial medicines. One thousand and six hundred drugs were screened using the ZEBOV-GP/HIV model, a pseudovirus formed by an HIV-core packed with the Zaire Ebola virus glycoprotein. We identified 12 gonadal hormone drugs with inhibitory activities in ZEBOV-GP/HIV entry at final concentration of 10 μmol x L(-1). Among them, three drugs exhibited strong activities with IC50 < 1 μmol x L(-1), such as toremifene citrate (IC50: 0.19 ± 0.02 μmol x L(-1)), tamoxifen citrate (IC50: 0.32 ± 0.01 μmol x L(-1)) and clomiphene citrate (IC50: 0.53 ± 0.02 μmol x L(-1)); seven drugs had moderate activities with IC50 between 1 and 10 μmol x L(-1), such as estradiol benzoate (IC50: 1.83 ± 5.69 μmol x L(-1)), raloxifene hydrochloride (IC50: 3.48 ± 0.07 μmol x L(-1)), equilin (IC50: 4.00 ± 9.94 μmol x L(-1)), estradiol (IC50: 5.26 ± 9.92 μmol x L(-1)), quinestrol (IC50: 6.36?5.37 gmol-L1), estrone (IC50: 6.87 ± 0.03 μmol-L1) and finasteride (IC50: 9.94 ± 0.45 μmol x L(-1)); two drugs, hexestrol (IC50: 14.20 ± 0.55 μmol x L(-1)) and chlormadinone acetate (IC50: 24.60 ± 0.36 μmol x L(-1)), had weak activities against ZEBOV. Further, toremifene citrate, tamoxifen citrate, clomiphene citrate, raloxifene hydrochloride and quinestrol could block both pseudovirus type Sudan ebola virus (SEBOV-GP/HIV) and Marburg virus (MARV-GP/HIV) entries.
Antiviral Agents ; pharmacology ; Drug Evaluation, Preclinical ; Ebolavirus ; drug effects ; physiology ; Hemorrhagic Fever, Ebola ; Humans ; Marburgvirus ; drug effects ; physiology ; Selective Estrogen Receptor Modulators ; pharmacology ; Virus Internalization ; drug effects

Ebola virus, the cause of severe and fatal hemorrahagic fever in humans, belongs to filovirus family. This study was designed to establish a cell-based screening and evaluation system in the pharmacological study of antivirus compounds. Three reporter systems were established with recombinant pseudoviral luciferase of HIV core (pNL4-3.Luc.R(-)E(-)) packed with filovirus glycoprotein (EBOV-Zaire GP/HIV-luc, EBOV-Sudan GP/HIV-luc and Marburg GP/HIV-luc), which are required for virus entry of cells. The level of filovirus entry was determined by the expression of luciferase reporter gene in the infected cells. For screening of filovirus entry inhibitors, the vesicular stomatitis G packed pseudovirions (VSVG/HIV-luc) was used to determine the compound specificity. The results of known filovirus entry inhibitors demonstrated successful establishment of the new model systems, which would be useful in high throughput screening of anti-filovirus drugs in the future.
Antiviral Agents ; pharmacology ; Drug Evaluation, Preclinical ; methods ; Ebolavirus ; drug effects ; physiology ; Genes, Reporter ; Glycoproteins ; genetics ; Hemorrhagic Fever, Ebola ; Humans ; Luciferases ; Viral Proteins ; genetics ; Virus Internalization ; drug effects

In 2012, a new SARS-like coronavirus emerged in the Middle East, namely the Middle East respiratory syndrome coronavirus (MERS-CoV). It has caused outbreaks with high mortality. During infection of target cell, MERS-CoV S protein S1 subunit binds to the cellular receptor (DPP4), and its S2 subunit HR1 and HR2 regions intact with each other to form a stable six-helix bundle to mediate the fusion between virus and target cell membranes. Hence, blocking the process of six-helix bundle formation can effectively inhibit MERS-CoV entry into the target cells. This review focuses on the recent advance in the development of peptidic entry inhibitors targeting the MERS-CoV S2 subunit.
Antiviral Agents ; pharmacology ; Coronavirus Infections ; drug therapy ; Dipeptidyl Peptidase 4 ; metabolism ; Drug Design ; Humans ; Middle East Respiratory Syndrome Coronavirus ; drug effects ; physiology ; Peptides ; pharmacology ; Spike Glycoprotein, Coronavirus ; metabolism ; Virus Internalization ; drug effects

The respiratory syncytial virus (RSV) is one of the most common causes of acute infection of the lower respiratory tract among children. For viruses in the Paramyxoviridae subfamily, membrane fusion requires a specific interaction between two glycoproteins: the fusion protein and attachment protein. Membrane fusion of the RSV appears to be unique among paramyxoviruses in that fusion is accomplished by the fusion protein alone without help from the attachment protein. Here, we review recent achievements and advances in the study of membrane fusion triggered by the RSV published in high-impact-factor journals. We also review and make a comparative analysis of the popular hypotheses regarding membrane fusion of the RSV. Finally, we discuss the "hot topics" in current research and controversial data published in recent years in the hope of providing references for Chinese researchers.
Animals ; Humans ; Respiratory Syncytial Virus Infections ; virology ; Respiratory Syncytial Viruses ; genetics ; physiology ; Viral Fusion Proteins ; genetics ; metabolism ; Virus Internalization

Japanese encephalitis virus (JEV) is a pathogenic mosquito-borne flavivirus which is responsible for outbreaks of severe viral encephalitis. The cellular entry of JEV is a prerequisite for Japanese encephalitis, so the understanding of its underlying mechanisms will provide more approaches for treating such disease. In recent years, increasing research has been conducted to investigate the mechanisms of cellular entry of JEV, and the results of research on other flavivirus have expanded the research directions for JEV. More methods will be used to suppress JEV infection because of the development of E protein antibodies and the discovery of several inhibitors of the cellular entry process. This review will summarize the recent advances in the mechanisms of JEV cellular entry and membrane fusion.
Animals ; Biomedical Research ; trends ; Encephalitis Virus, Japanese ; genetics ; physiology ; Encephalitis, Japanese ; virology ; Humans ; Virus Internalization

The research on intracellular trafficking of adenovirus has been described mainly through observations of subgroup C adenoviruses in transformed cell lines. The basic elements of the trafficking pathway include binding to receptors at the cell surface, internalization by endocytosis, lysis of the endosomal membrane, escape to the cytosol, intracellular trafficking along microtubules, nuclear pore docking, and viral genome translocation into the nucleus. More than 80% of the adenovirus genome is delivered to the nucleus in a highly efficient manner in approximately 1 h. However, exceptions to this trafficking pattern have been noted, including: variations based on target cell type, cell physiology, and adenovirus serotype. This review summarizes mechanism of adenovirus infection pathway and intracellular trafficking, providinging a foundation for the development of clinical adenoviral vector.
Adenoviridae ; physiology ; Cell Membrane ; virology ; Cell Nucleus ; virology ; Cytoplasm ; virology ; Endocytosis ; Endosomes ; virology ; Genetic Vectors ; Humans ; Microtubules ; Virus Internalization