Abstract:
:Ebola virus (EBOV) causes severe hemorrhagic fever, for which therapeutic options are not available. Preventing the entry of EBOV into host cells is an attractive antiviral strategy, which has been validated for HIV by the FDA approval of the anti-HIV drug enfuvirtide. To identify inhibitors of EBOV entry, the EBOV envelope glycoprotein (EBOV-GP) gene was used to generate pseudotype viruses for screening of chemical libraries. A benzodiazepine derivative (compound 7) was identified from a high-throughput screen (HTS) of small-molecule compound libraries utilizing the pseudotype virus. Compound 7 was validated as an inhibitor of infectious EBOV and Marburg virus (MARV) in cell-based assays, with 50% inhibitory concentrations (IC(50)s) of 10 μM and 12 μM, respectively. Time-of-addition and binding studies suggested that compound 7 binds to EBOV-GP at an early stage during EBOV infection. Preliminary Schrödinger SiteMap calculations, using a published EBOV-GP crystal structure in its prefusion conformation, suggested a hydrophobic pocket at or near the GP1 and GP2 interface as a suitable site for compound 7 binding. This prediction was supported by mutational analysis implying that residues Asn69, Leu70, Leu184, Ile185, Leu186, Lys190, and Lys191 are critical for the binding of compound 7 and its analogs with EBOV-GP. We hypothesize that compound 7 binds to this hydrophobic pocket and as a consequence inhibits EBOV infection of cells, but the details of the mechanism remain to be determined. In summary, we have identified a novel series of benzodiazepine compounds that are suitable for optimization as potential inhibitors of filoviral infection.
journal_name
J Viroljournal_title
Journal of virologyauthors
Basu A,Li B,Mills DM,Panchal RG,Cardinale SC,Butler MM,Peet NP,Majgier-Baranowska H,Williams JD,Patel I,Moir DT,Bavari S,Ray R,Farzan MR,Rong L,Bowlin TLdoi
10.1128/JVI.01456-10subject
Has Abstractpub_date
2011-04-01 00:00:00pages
3106-19issue
7eissn
0022-538Xissn
1098-5514pii
JVI.01456-10journal_volume
85pub_type
杂志文章abstract::We have examined the transcriptional utilization of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) under differentiating conditions by using the embryonal carcinoma cell line NTERA-2. NTERA-2 cells undergo two distinct pathways of terminal differentiation, to a neuronal phenotype in respons...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.4.2268-2273.1992
更新日期:1992-04-01 00:00:00
abstract:UNLABELLED:The HIV-1 envelope glycoprotein (Env) is a trimer of gp120-gp41 heterodimers and is essential for viral entry. The gp41 subunit in native, prefusion trimeric Env exists in a metastable conformation and attains a stable six-helix bundle (6-HB) conformation comprised of a trimer of N-heptad repeat (NHR) and C-...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00494-14
更新日期:2014-09-01 00:00:00
abstract::Positional homologs to the UL51 open reading frame of herpes simplex virus type 1 have been identified throughout the herpesvirus family. However, no respective protein has so far been described for any of the herpesviruses. With rabbit antisera directed against oligopeptides predicted to comprise antigenic regions of...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.7.5635-5638.1997
更新日期:1997-07-01 00:00:00
abstract::The DNA sequence of 3,240 nucleotides of the XbaI G fragment located in the unique long (UL) region of the equine herpesvirus 1 genome revealed two major open reading frames (ORFs) designated UL3 and UL4. The UL3 ORF of 470 amino acids (aa) maps at nucleotides (nt) 4450 to 3038 from the long terminus, and its predicte...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.9.5363-5372.1992
更新日期:1992-09-01 00:00:00
abstract::In this study, we characterized the viral determinants of coreceptor usage in relation to susceptibility to antibody-mediated neutralization or enhancement of infectivity by using chimeras of three highly related human immunodeficiency virus type 1 (HIV-1) isolates of different phenotypes. We found that the V3 region ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.6.2827-2834.2002
更新日期:2002-03-01 00:00:00
abstract::Capsid (core) assembly is essential for hepatitis B virus (HBV) replication. We hypothesize that assembly kinetics and stability are tuned for optimal viral replication, not maximal assembly. Assembly effectors (AEfs) are small molecules proposed to disrupt this balance by inappropriately enhancing core assembly. Guid...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03014-12
更新日期:2013-03-01 00:00:00
abstract:UNLABELLED:The extreme stability of the latent HIV-1 reservoir in the CD4(+) memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific ge...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00571-15
更新日期:2015-07-01 00:00:00
abstract::The structural polypeptides of purified Plodia interpunctella granulosis virus were analyzed by three different two-dimensional gel systems. Isoelectric focusing followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis allowed resolution of 53 acidic polypeptides in the enveloped nucleocapsid of the virus...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.60.1.82-89.1986
更新日期:1986-10-01 00:00:00
abstract::Alfalfa mosaic virus (AMV) and ilarvirus RNAs are infectious only in the presence of the viral coat protein; therefore, an understanding of coat protein's function is important for defining viral replication mechanisms. Based on in vitro replication experiments, the conformational switch model states that AMV coat pro...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.9.5752-5761.2005
更新日期:2005-05-01 00:00:00
abstract::To study fundamental aspects of RNA recombination, an in vivo RNA recombination system was established. This system allowed the efficient generation of recombinant cytopathogenic pestiviruses after transfection of synthetic, nonreplicatable, subgenomic transcripts in cells infected with a replicating noncytopathogenic...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.12.6271-6281.2004
更新日期:2004-06-01 00:00:00
abstract::Cowpox virus (CPXV) belongs to the genus Orthopoxvirus in the Poxviridae family. It infects a broad range of vertebrates and can cause zoonotic infections. CPXV has the largest genome among the orthopoxviruses and is therefore considered to have the most complete set of genes of all members of the genus. Since CPXV ha...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02385-13
更新日期:2014-01-01 00:00:00
abstract::Coevolution of virus and host is a process that emerges in persistent virus infections. Here we studied the coevolutionary development of coxsackievirus B3 (CVB3) and cardiac myocytes representing the major target cells of CVB3 in the heart in a newly established persistently CVB3-infected murine cardiac myocyte cell ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00621-11
更新日期:2011-12-01 00:00:00
abstract::Infectious bursal disease virus (IBDV) is a double-stranded RNA (dsRNA) virus of the Birnaviridae family. Its two genome segments are encapsidated together with multiple copies of the viral RNA-dependent RNA polymerase, VP1, in a single-shell capsid that is composed of VP2 and VP3. In this study we identified the doma...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.22.11301-11311.2002
更新日期:2002-11-01 00:00:00
abstract::With the aid of three monoclonal antibodies (MAbs), a glycoprotein specifically localized to the outer envelope of vaccinia virus was shown to be encoded by the A33R gene. These MAbs reacted with a glycosylated protein that migrated as 23- to 28-kDa and 55-kDa species under reducing and nonreducing conditions, respect...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.6.3753-3762.1996
更新日期:1996-06-01 00:00:00
abstract::DNA was extracted from [(3)H]thymidine-labeled Marek's disease virus (MDV) and purified by two cycles of CsCl gradient centrifugation in a fixed-angle rotor. The DNA was transcribed in vitro into (32)P-labeled complementary RNA (cRNA). MDV cRNA did not hybridize with DNA from chicken embryo fibroblast cultures or from...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.12.4.841-846.1973
更新日期:1973-10-01 00:00:00
abstract::Western equine encephalitis virus (WEEV; Togaviridae, Alphavirus) is an enveloped RNA virus that is typically transmitted to vertebrate hosts by infected mosquitoes. WEEV is an important cause of viral encephalitis in humans and horses in the Americas, and infection results in a range of disease, from mild flu-like il...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00876-10
更新日期:2010-10-01 00:00:00
abstract::Human metapneumovirus (hMPV), a recently described paramyxovirus, is a major etiological agent for lower respiratory tract disease in young children that can manifest with severe cough, bronchiolitis, and pneumonia. The hMPV fusion glycoprotein (F) shares conserved functional domains with other paramyxovirus F protein...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.16.10678-10689.2005
更新日期:2005-08-01 00:00:00
abstract::We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.15.7984-7989.2004
更新日期:2004-08-01 00:00:00
abstract::Following respiratory syncytial virus (RSV) challenge, mice immunized with RSV G or with formalin-inactivated RSV (FI-RSV) exhibit severe disease associated with type 2 cytokine production and pulmonary eosinophilia. This has led to the proposal that the presence of RSV G is the factor in FI-RSV that induces disease-e...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.11.6024-6032.2004
更新日期:2004-06-01 00:00:00
abstract::Recent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenz...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01675-10
更新日期:2010-12-01 00:00:00
abstract::Infection of primary fibroblasts with human cytomegalovirus (HCMV) causes a rapid stabilization of the cellular protein p53. p53 is a major effector of the cellular damage response, and activation of this transcription factor can lead either to cell cycle arrest or to apoptosis. Viruses employ many tactics to avoid p5...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00505-06
更新日期:2006-09-01 00:00:00
abstract::The preintegration complex of human immunodeficiency virus type 1 (HIV-1) is a large nucleoprotein complex containing viral nucleic acids in association with products of the viral gag and pol genes. One of these proteins, integrase, is absolutely required for the integration and formation of the provirus. Although HIV...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.11.6863-6865.1993
更新日期:1993-11-01 00:00:00
abstract::It has been proposed recently that the cell surface peptidase CD26 acts in concert with CD4, the human immunodeficiency virus (HIV) primary receptor molecule, to mediate HIV entry into permissive cells. We have failed to detect significant levels of CD26 cell surface expression and enzymatic activity in a number of co...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.10.6535-6546.1994
更新日期:1994-10-01 00:00:00
abstract::The proteolytic enzyme, thermolysin, degraded the external segment of the membrane glycoprotein of intact vesicular stomatitis (VS) virions but left behind a small nonglycosylated fragment, presumably embedded in the virion membrane. Other proteases generated membrane-associated glycoprotein fragments differing somewh...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.16.2.237-240.1975
更新日期:1975-08-01 00:00:00
abstract::We identified the transcriptional coactivator FHL2 as a novel target of the human papillomavirus type 16 (HPV-16) E7 oncoprotein, which plays a major role in cell transformation. The interaction with FHL2 is abolished by mutations in conserved regions 1 and 2 and in the C-terminal zinc finger domain of E7, all require...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01699-06
更新日期:2007-01-01 00:00:00
abstract::Many viral fusion proteins are primed by proteolytic cleavage near their fusion peptides. While the coronavirus (CoV) spike (S) protein is known to be cleaved at the S1/S2 boundary, this cleavage site is not closely linked to a fusion peptide. However, a second cleavage site has been identified in the severe acute res...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00079-09
更新日期:2009-08-01 00:00:00
abstract::We studied the effect of filovirus infection on host cell gene expression by characterizing the regulation of gene expression responses in human liver cells infected with Zaire Ebolavirus (ZEBOV), Reston Ebolavirus (REBOV), and Marburgvirus (MARV), using transcriptional profiling and bioinformatics. Expression microar...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.80.6.3009-3020.2006
更新日期:2006-03-01 00:00:00
abstract::Human parainfluenza type 2 virus (hPIV-2)-infected HeLa (HeLa-CA) cells and hPIV-2 V-expressing HeLa (HeLa-V) cells show high resistance to alpha/beta interferons (IFN-alpha/beta) irrespective of whether vesicular stomatitis virus or Sindbis virus is used as a challenge virus. When Sindbis virus is used, these cells s...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.19.9165-9176.2001
更新日期:2001-10-01 00:00:00
abstract::Human cytomegalovirus (HCMV) has emerged as a clinically opportunistic pathogen that targets multiple types of ocular cells and tissues, including the iris region of the uveal tract during anterior uveitis. In this report, we used primary cultures of human iris stroma (HIS) cells derived from human eye donors to inves...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00109-15
更新日期:2015-05-01 00:00:00
abstract::The immediate-early gene ie2 of murine cytomegalovirus was characterized. The 1.75-kb ie2 transcript is spliced from three exons, of 78, 124, and 1,283 nucleotides, which are separated by introns of 1,245 and 364 nucleotides. An ATG codon located in the third exon leads into an open reading frame of 391 codons. Immedi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.3.1638-1643.1991
更新日期:1991-03-01 00:00:00