Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phylogenetic relationships among the Paramyxoviridae, a broad family of viruses whose members cause devastating diseases of wildlife, livestock, and humans, were examined with both fusion (F) and matrix (M) protein-coding sequences. Neighbor-joining trees of F and M protein sequences showed that the Paramyxoviridae was divided into the two traditionally recognized subfamilies, the Paramyxovirinae and the Pneumovirinae. Within the Paramyxovirinae, the results also showed groups corresponding to three currently recognized genera: Respirovirus, Morbillivirus, and Rubulavirus. The relationships among the three genera of the Paramyxovirinae were resolved with M protein sequences and there was significant bootstrap support (100%) showing that members of the genus Respirovirus and the genus Morbillivirus were more closely related to each other than to members of the genus Rubulavirus. Both F and M phylogenies showed that Newcastle disease virus (NDV) was more closely related to the genus Rubulavirus than to the other two genera but were consistent with the proposal (B. S. Seal et al., 2000, Virus Res. 66, 1-11) that NDV be classified as a separate genus within the Paramyxovirinae. Both F and M phylogenies were also consistent with the proposal (L. Wang et al., 2000, J. Virol 74, 9972-9979) that Hendra virus be classified as a new genus closely related and basal to the genus Morbillivirus. Rinderpest was most closely related to measles and a more derived virus than to canine distemper virus, phocine distemper virus, or dolphin morbillivirus.
Mol Phylogenet Evol 2001 Oct
PMID:Molecular evolution of viral fusion and matrix protein genes and phylogenetic relationships among the Paramyxoviridae. 1160 43

Vaccination with autologous cancer cells expressing a potent foreign antigen is promising for immunotherapy of tumors. A construct was obtained to transfect cancer cells with the hemagglutinin-neuraminidase (HN) gene of the Newcastle disease virus (NDV). Specific primers were designed, and the HN cDNA was amplified from RNA isolated from the allantoid fluid of NDV-infected embryonated chicken eggs. The amplified fragment was cloned in pCR2.1, sequenced, and recloned in expression vector pCDNA3.1/Zeo(+). The resulting construct was used to transfect mouse myeloma cells SP2/0. Production of HN was checked by ELISA and by a neuraminidase activity assay. Cell agglutination on ice was proposed as a test for surface HN.
Mol Biol (Mosk)
PMID:[Expression of a cloned hemagglutinin-neuraminidase gene from Newcastle disease virus in murine myeloma cells]. 1160 46

Paramyxovirus fusion proteins have two heptad repeat domains, HR1 and HR2, that have been implicated in the fusion activity of the protein. Peptides from these two domains form a six-stranded, coiled-coil with the HR1 sequences forming a central trimer and three molecules of the HR2 helix located within the grooves in the central trimer (Baker et al., 1999, Mol. Cell 3, 309; Zhao et al. 2000, Proc. Natl. Acad. Sci. USA 97, 14172). Nonconservative mutations were made in the HR2 domain of the Newcastle disease virus fusion protein in residues that are likely to form contacts with the HR1 core trimer. These residues form the hydrophobic face of the helix and adjacent residues ("a" and "g" positions in the HR2 helical wheel structure). Mutant proteins were characterized for effects on synthesis, steady-state levels, proteolytic cleavage, and surface expression as well as fusion activity as measured by syncytia formation, content mixing, and lipid mixing. While all mutant proteins were transport competent and proteolytically cleaved, these mutations did variously affect fusion activity of the protein. Nonconservative mutations in the "g" position had no effect on fusion. In contrast, single changes in the middle "a" position of HR2 inhibited lipid mixing, content mixing, and syncytia formation. A single mutation in the more carboxyl-terminal "a" position had minimal effects on lipid mixing but did inhibit content mixing and syncytia formation. These results are consistent with the idea that the HR2 domain is involved in posttranslational interactions with HR1 that mediate the close approach of membranes. These results also suggest that the HR2 domain, particularly the carboxyl-terminal region, plays an additional role in fusion, a role related to content mixing and syncytia formation.
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PMID:Mutational analysis of the membrane proximal heptad repeat of the newcastle disease virus fusion protein. 1168 56

A lectin-carbohydrate recognition event without enzymatic function is proposed as molecular basis for an important innate immune response to enveloped viruses. It involves the hemagglutinin-neuraminidase (HN) glycoprotein of Newcastle disease virus (NDV) and sialic acid expressing cellular receptors on human natural interferon (IFN) alpha producing cells. This conclusion is based on two types of experimental evidence: (a) strong UV irradiation of NDV, which destroyed the cell binding and hemadsorption (HAd) but not the neuraminidase (NA) activity of HN, also destroyed its IFN-alpha inducing activity; (b) DNA transfectants expressing HN mutant molecules with greatly reduced NA but not HAd activity induced IFN-alpha while transfectants expressing HN mutant molecules with greatly reduced NA and HAd activity were incapabable of inducing IFN-alpha in human peripheral blood mononuclear cells. The results clarify molecular mechanisms involved in pattern recognition during innate immune responses.
J Mol Med (Berl) 2002 Jul
PMID:Stimulation of human natural interferon-alpha response via paramyxovirus hemagglutinin lectin-cell interaction. 1211 Sep 50

Transcription factors of the interferon regulatory factor (IRF) family have been identified as critical mediators of early inflammatory gene transcription in infected cells. We recently determined that, besides IRF-3 and IRF-7, IRF-5 serves as a direct transducer of virus-mediated signaling. In contrast to that mediated by the other two IRFs, IRF-5-mediated activation is virus specific. We show that, in addition to Newcastle disease virus (NDV) infection, vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) infection activates IRF-5, leading to the induction of IFNA gene subtypes that are distinct from subtypes induced by NDV. The IRF-5-mediated stimulation of inflammatory genes is not limited to IFNA since in BJAB/IRF-5-expressing cells IRF-5 stimulates transcription of RANTES, macrophage inflammatory protein 1 beta, monocyte chemotactic protein 1, interleukin-8, and I-309 genes in a virus-specific manner. By transient- transfection assay, we identified constitutive-activation (amino acids [aa] 410 to 489) and autoinhibitory (aa 490 to 539) domains in the IRF-5 polypeptide. We identified functional nuclear localization signals (NLS) in the amino and carboxyl termini of IRF-5 and showed that both of these NLS are sufficient for nuclear translocation and retention in infected cells. Furthermore, we demonstrated that serine residues 477 and 480 play critical roles in the response to NDV infection. Mutation of these residues from serine to alanine dramatically decreased phosphorylation and resulted in a substantial loss of IRF-5 transactivation in infected cells. Thus, this study defines the regulatory phosphorylation sites that control the activity of IRF-5 in NDV-infected cells and provides further insight into the structure and function of IRF-5. It also shows that the range of IRF-5 immunoregulatory target genes includes members of the cytokine and chemokine superfamilies.
Mol Cell Biol 2002 Aug
PMID:Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes. 1213 84

The phosphoprotein (P) gene of a heat stable Newcastle disease virus (NDV) was cloned, sequenced and expressed in Escherichia coli. SDS-PAGE analysis of the recombinant P protein (395 amino acids) and a C-terminal extension derivative (424 amino acids), gave rise to two distinct protein bands with molecular masses of approximately 53-55 and 56-58 kDa, respectively, which are approximately 26-30% heavier than those calculated from the deduced amino acid sequences. The differences in molecular mass on SDS-PAGE are thought to be attributed to the acidic nature of the P protein (pI=6.27) and also the different degrees of phosphorylation in the prokaryotic cell. Amino acid sequence comparison of the P protein among the published NDV strains showed that they were highly conserved particularly at the putative phosphorylation sites.
J Biochem Mol Biol Biophys 2002 Apr
PMID:Cloning and expression of the phosphoprotein gene of Newcastle disease virus in Escherichia coli. 1218 67

The three-dimensional structure of the haemagglutinin-neuraminidase (HN) from a human parainfluenza virus is described at ca 2.0 A resolution, both in native form and in complex with three substrate analogues. In support of earlier work on the structure of the homologous protein from the avian pathogen Newcastle disease virus (NDV), we observe a dimer of beta-propellers and find no evidence for spatially separated sites performing the receptor-binding and neuraminidase functions of the protein. As with the NDV HN, the active site of the HN of parainfluenza viruses is structurally flexible, suggesting that it may be able to switch between a receptor-binding state and a catalytic state. However, in contrast to the NDV structures, we observe no ligand-induced structural changes that extend beyond the active site and modify the dimer interface.
J Mol Biol 2004 Jan 30
PMID:Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III. 1472 48

PV701 is an attenuated, non-recombinant, oncolytic strain of Newcastle disease virus that displays preclinical intravenous (i.v.) efficacy. PV701 selectively lyses tumor cells versus normal cells based on tumor-specific defects in the interferon-mediated antiviral response. In three phase I trials in 113 patients, the effects of dose, schedule and i.v. infusion rate were evaluated. Three types of adverse events were seen: flu-like, tumor-site-specific and those occurring during infusion. The first PV701 dose desensitized the patient to the side effects of further doses, allowing a 5- to 10-fold increase in the maximum-tolerated dose for subsequent doses compared with the first dose. Tumor responses were first noted at the higher doses achieved using desensitization. In 95 evaluable patients, there were ten responses (six major and four minor), with five of these responses occurring in the most recent trial of 18 patients that employed desensitization, high repeat doses and a slower infusion rate. Phase II studies are planned.
Curr Opin Mol Ther 2003 Dec
PMID:Overview of phase I studies of intravenous administration of PV701, an oncolytic virus. 1475 88

Paramyxovirus infections can be detected worldwide with some emerging zoonotic viruses and currently there are no specific therapeutic treatments or vaccines available for many of these diseases. Recent studies have demonstrated that peptides derived from the two heptad repeat regions (HR1 and HR2) of paramyxovirus fusion proteins could be used as inhibitors of virus fusion. The mechanism underlying this activity is in accordance with that of class I virus fusion proteins, of which human immunodeficiency virus (HIV) and influenza virus fusion proteins are members. For class I virus fusion proteins, the HR1 fragment binds to HR2 to form a six-helix bundle with three HR1 fragments forming the central coiled bundle surrounded by three coiled HR2 fragments in the post fusion conformational state (fusion core). It is hypothesized that the introduced exogenous HR1 or HR2 can compete against their endogenous counterparts, which results in fusion inhibition. Using Newcastle disease virus (NDV) as a model, we designed several protein inhibitors, denoted HR212 as well asHR121 and 5-Helix, which could bind the HR1 or HR2 region of fusion protein, respectively. All the proteins were expressed and purified using a GST-fusion expression system in Escherichia coli. The HR212 or GST-HR212 protein, which binds the HR1 peptide in vitro, displayed inhibitory activity against NDV-mediated cell fusion, while the HR121 and 5-Helix proteins, which bind the HR2 peptide in vitro, inhibited virus fusion from the avirulent NDV strain when added before the cleavage of the fusion protein. These results showed that the designed HR212, HR121 or 5-Helix protein could serve as specific antiviral agents. These data provide additional insight into the difference between the virulent and avirulent strains of NDV.
J Mol Biol 2005 Dec 02
PMID:Design and characterization of viral polypeptide inhibitors targeting Newcastle disease virus fusion. 1625 71

We undertook a Phase I/II trial in patients with apparent recurrent glioblastoma multiforme (GBM) based on imaging studies to determine the safety and tumor response of repetitive intravenous administration of NDV-HUJ, the oncolytic HUJ strain of Newcastle disease virus. The first part of the study utilized an accelerated intrapatient dose-escalation protocol with one-cycle dosage steps of 0.1, 0.32, 0.93, 5.9, and 11 billion infectious units (BIU) of NDV-HUJ (1 BIU = 1 x 10(9) EID(50) 50% egg infectious dose) followed by three cycles of 55 BIU. Virus was administered by intravenous infusion over 15 min. In the second part, patients received three cycles of 11 BIU. All patients without progressive disease were maintained with two doses of 11 BIU iv weekly. Eleven of the 14 enrolled patients (11-58 years, Karnofsky performance scale 50-90%) received treatment. Toxicity was minimal with Grade I/II constitutional fever being seen in 5 patients. Maximum tolerated dose was not achieved. Anti-NDV hemagglutinin antibodies appeared within 5-29 days. NDV-HUJ was recovered from blood, saliva, and urine samples and one tumor biopsy. One patient achieved a complete response. Intravenous NDV-HUJ is well tolerated. The findings of good tolerability and encouraging responses warrant the continued evaluation of NDV-HUJ in GBM, as well as other cancers.
Mol Ther 2006 Jan
PMID:Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. 1625 82


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