OBJECTIVETo study the inhibitory activities of 3-trifluoromethyl benzamide derivatives against the entry of H5N1 influenza viruses.

METHODSThe lead compound was structurally modified to obtain 3 compounds with inhibitory activities against H5N1 influenza viruses. Specs compound librany was screened and 4 compounds were identified to have such inhibitory activities. The inhibitory activities of these compounds were tested at a celluar level against H5N1 influenza viruses.

RESULTS AND CONCLUSIONThe compounds 1a, 1b, 1e and 1f showed signifcant inhibitory activities against the entry of A/AnHui/1/2005 pseudovirus into the target cells with an IC50 value of 4.7 ± 0.3 µmol/L.

Antiviral Agents ; pharmacology ; Benzamides ; pharmacology ; Humans ; Influenza A Virus, H5N1 Subtype ; drug effects ; physiology ; Influenza, Human ; Virus Internalization ; drug effects

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

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

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

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

To reveal the effects of disulfide bridges in rubella virus glycoprotein E1 on the membrane fusion activity, the recombinant plasmid pBSK-SPE2E1 and site-directed mutagenesis to mutate 11 cysteines individually in the ectodomain of E1 to remove a disulfide bridge from the wild-type E1 were constructed. All mutants and the wild-type plasmid were expressed on BHK-21 cell. Giemsa Staining was used to show the polykaryon formed in the transfected BHK-21 cells. The cell surface expression efficiency of the plasmids was assayed with fluorescence-activated cell sorter (FACS). Hemadsorption was performed to detect the receptor recognition activity of the recombinant plasmids. The results showed that all the 10 disulfide bridges in the ectodomain of E1 played an important role in the process of the membrane fusion. The removal of any disulfide bridge resulted in the loss of the fusion activity. The disulfide formed by the 5th and the 8th cysteine might be critical for the interaction of E1 and E2. While the disulfide bridges formed by the 3rd, the 4th, and the 13th might influence the membrane fusion activity of E1 directly.
Cell Membrane ; drug effects ; Cysteine ; chemistry ; Disulfides ; chemistry ; pharmacology ; Flow Cytometry ; Membrane Fusion ; drug effects ; Mutagenesis, Site-Directed ; Rubella virus ; chemistry ; Viral Envelope Proteins ; chemistry ; Viral Fusion Proteins ; 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

OBJECTIVETo study the mechanism underlying the inhibitory effect of the anti-HIV peptide VIR576 on antigen-specific T cell activation.

METHODSCCK-8 assay was used to investigate the effect of VIR576 on the proliferation of splenocytes of OVA-specific DO11.10 Tg mice in response to chicken OVA. Hemolysis test, hemolysis inhibition assay and fluorescence binding assay were used to investigate the interaction of VIR576 with the transmembrane domain (TMD) of the T cell receptor (TCR).

RESULTSVIR576 inhibited HIV glycoprotein gp41 fusion peptide-mediated antigen specific T cell activation, and VIR576 itself also inhibited splenocyte proliferation in responses to OVA (P<0.05). Hemolysis test, hemolysis inhibition assay and fluorescence binding assay demonstrated that VIR576 suppressed TCR-TMD-mediated hemolysis and competitively inhibited Rho-VIR576 binding to TCR-TMD peptide.

CONCLUSIONVIR576 is effective in suppressing the antigen-specific T cell activation via TCR and can interact with TCR-TMD. VIR576 may serve as a potent microbicide candidate to block sexual transmission of HIV due to of its inhibitory effect on both HIV entry and antigen-specific T cell activation.

Animals ; Anti-HIV Agents ; pharmacology ; Cell Membrane ; metabolism ; HIV Infections ; prevention & control ; Humans ; Lymphocyte Activation ; drug effects ; Mice ; Receptors, Antigen, T-Cell ; immunology ; Sincalide ; analysis ; Spleen ; cytology ; immunology ; T-Lymphocytes ; immunology ; Virus Internalization ; drug effects

Treatments for chronic hepatitis C has evolved significantly in the past 15 years. The standard of care (SOC) is peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks in patients infected with HCV genotype 1 or 2/3, respectively. The treatment duration can be individualized based on the baseline viral load and the speed of the virologic response during treatment. However, current therapies are associated with side effects, complications, and poor patient tolerability. Therefore, there is an urgent need to identify better strategies for treating this disease. An improved sustained virologic response (SVR) can be achieved with new HCV-specific inhibitors against NS3/4A and NS5B polymerases. Recent trials have found SVR rates in patients with HCV genotype 1 infection of 61~68% and 67~75% for combining the SOC with the protease inhibitors telaprevir and boceprevir, respectively. Several new HCV-specific inhibitors such as protease inhibitors and nucleoside and non-nucleoside polymerase inhibitors as well as non-HCV-specific compounds with anti-HCV activity are currently in clinical evaluation. In this review we discuss these new treatments for chronic hepatitis C.
Antiviral Agents/*therapeutic use ; DNA-Directed RNA Polymerases/antagonists & inhibitors/metabolism ; Hepatitis C, Chronic/*drug therapy ; Humans ; Interferons/therapeutic use ; Nucleotides/chemistry/therapeutic use ; Protease Inhibitors/*therapeutic use ; Viral Nonstructural Proteins/antagonists & inhibitors/metabolism ; Virus Internalization/drug effects

This study is to establish a cell-based model targeting to neuraminidase (NA) of the 2009 H1N1 influenza A virus. NA is an influenza virus structural protein with enzymatic activity of the cleavage of HA-sialic acid interaction to release new viral particles from cells. A model of HIV-1 (pNL4-3.Luc.R(-)E(-)) based pseudovirions packed with HA [hemagglutinin, A/VietNam/1203/2004 (H5N1)] and NA [A/California/04/2009 (H1N1)] was established to evaluate compounds activities on NA function. The viral release can be blocked by neuraminidase inhibitors, oseltamivir and oseltamivir carboxylate, with IC50 of (61 +/- 31) nmol L(-1) and (5.5 +/- 2.9) nmol L(-1) respectively. A point mutation of H275Y on NA leads oseltamivir-resistance. This corresponding mutation was introduced into the system which was also confirmed by oseltamivir and oseltamivir carboxylate.
Cell Line, Tumor ; Drug Resistance, Viral ; genetics ; Enzyme Inhibitors ; pharmacology ; HEK293 Cells ; HIV-1 ; genetics ; Hemagglutinin Glycoproteins, Influenza Virus ; genetics ; metabolism ; Humans ; Influenza A Virus, H1N1 Subtype ; drug effects ; genetics ; metabolism ; Influenza A Virus, H5N1 Subtype ; drug effects ; genetics ; metabolism ; Mutation ; Neuraminidase ; antagonists & inhibitors ; genetics ; metabolism ; Oseltamivir ; analogs & derivatives ; pharmacology ; Plasmids ; Transfection ; Virus Internalization