CHROMATIN TARGETS FOR CANCER THERAPY
Daniel A Engel, Associate Professor
Medicineuniversity Of Virginia Charlottesville
box 400195
charlottesville, Va 229044195
Grant 5R01CA087620-02 from National Cancer Institute IRG: ZCA1
Abstract: Applicant´s Description) Expression of the adenovirus ElA oncoprotein in budding yeast has provided a useful model for uncovering novel pathways involved in oncoprotein action. Remarkably, multiprotein complexes (SWI/SNF and HAT complexes) that mediate chromatin remodeling and transcriptional regulation are targeted by EIA, leading to the strong prediction that disruption their human counterparts is important in the development of cancer. Indeed, there is evidence from human systems that the development of cancer is associated with loss or disregulation of genes encoding components of several SWI/SNF and HAT complexes. Given the clear role of "chromatin dynamics" in cellular regulation, and its genetic involvement in oncogenesis, the pathways which control chromatin function may contain useful targets for anti-cancer drug therapy. This proposal seeks to extend previous work on oncogenesis-related pathways in yeast, and to identify novel compounds with anti-cancer therapeutic potential. Yeast strains with defined defects in chromatin remodeling functions will be subjected to high throughput screens of two libraries The "Diversity Set" of approximately 2000 compounds from the National Cancer Institute´s Developmental Therapeutics Program, and a library of approximately 6000 ethanolic botanical extracts available through the Markey Center for Cell Signaling at the University of Virginia. The proven utility of Saccharomyces cerevisiae for illuminating novel oncogenesis-related pathways will allow genetic dissection of the action of novel lead compounds from the drug screens. Lead compounds will be tested further in mammalian cell culture systems to examine their potential as therapeutic agents, and their specific effects on mammalian chromatin dynamics
Keywords: Saccharomyces cerevisiae, antineoplastic, cell line, chromatin, drug discovery /isolation, drug screening /evaluation, plant extract high throughput technology
Project start date: 2000-07-01
Project end date: 2003-06-30
5R01CA087620-02 (2001): $266400
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Daniel A Engel
Development Of Yeast-Based Assays For Anti-influenza Drug Discovery
Daniel A Engel, Associate Professor
Microbiologyuniversity Of Virginia Charlottesville
box 400195
charlottesville, Va 229044195
Grant 1R01AI071341-01 from National Institute Of Allergy And Infectious Diseases IRG: ZAI1
Abstract: Yeast-based growth assays will be used to establish high-throughput screening (HTS) procedures for novel anti-influenza therapeutics. The targets for HTS will be the influenza A NS1 and M2 proteins, and the cellular p58 protein. NS1 and M2 have been shown to induce pronounced growth inhibition ("toxicity") when expressed in S. cerevisiae. Therefore chemical compounds that block the function of these proteins in yeast are expected to restore growth. Previously we have shown that the adenovirus E1A protein is toxic in yeast and that it is possible to screen for small molecules that reverse this effect. We have established yeast carrying deletions of the PDR1 and PDR3 genes, which control drug efflux. pdr1/pdr3 double mutants retain small molecules efficiently and allow screening of numerous diverse compounds. The development of the HTS for NS1 and M2 will involve three phases. First, expression of NS1 and M2 in the pdr1/pdr3 genetic background will be optimized such that a robust growth-inhibitory phenotype can be observed. This will be achieved using a variety of recombinant expression vectors and media conditions. Second, microtiter plate assays will be developed that allow clear differentiation between growth inhibition and growth restoration. Third, the microtiter plate assay will be automated using a functioning high-throughput robitcs station at the University of Virginia School of Medicine. An additional HTS procedure involving the cellular p58 protein will also be established. p58 is released during influenza infection and binds to protein kinase R (PKR), thereby preventing PKR from down regulating viral protein synthesis. In yeast, PKR is highly toxic and co-expression of p58 can completely block this toxicity, resulting in normal growth. Therefore compounds that interfere with p58 binding to PKR will result in PKR-induced toxicity. Such compounds would be expected to release PKR from p58 in virus-infected cells, thereby inhibiting virus replication. Again using our pdr1/pdr3 genetic background we will establish expression conditions for PKR-induced toxicity and p58 inhibition of PKR. This system will be used to establish microtiter plate assays and robotics screening
Keywords: drug discovery /isolation, influenza, protein, yeast conditioning, genetics, small molecule
Project start date: 2006-03-01
Project end date: 2008-08-31
1R01AI071341-01 (2006): $665597
ADENOVIRUS E1A PROTEIN AND THE SWI/SNF COMPLEX
Daniel A Engel, Associate Professor
Microbiologyuniversity Of Virginia Charlottesville
box 400195
charlottesville, Va 229044195
Grant 2R01CA060675-06A1 from National Cancer Institute IRG: VR
Abstract: The adenovirus E1A protein induces imortalization and transformation of cells in culture and is therefore an excellent model for the study of cellular transformation. E1A binds specific cell proteins including the retinoblastoma protein (Rb) and p300/CBP proteins that control transcription, in part, by altering chromatin structure. E1A inhibits the function of the chromatin remodeling complex SWI/SNF, which interacts with Rb protein and possibly p300. Specific aim 1 proposes to define and characterize the mammalian SWI/SNF complex with respect to its role in regulation of transcription. It will be determined how the complex inhibits c-fos expression at the transcriptional level. The structural changes that accompany the inhibition of c-fos gene activity will be characterized, and assays will be developed to measure the physical association of SWI/SNF with specific mammalian promoters in vivo. Studies will characterize the effects of E1A on SWI/SNF processes. Specific aim 2 will use a yeast genetic approach to understand E1A inhibition of the SWI/SNF complex. The yeast proteins that interact with E1A will be identified and their influence on E1A activity will be determined. Similar studies will then be conducted in mammalian cells using the information gained from the yeast system
Keywords: Adenoviridae, cell growth regulation, protein structure /function, transcription factor, virus protein cAMP response element binding protein, chromatin, fungal genetics, fungal protein, gene induction /repression, nucleic acid sequence, protein protein interaction, protooncogene molecular cloning, yeast
Project start date: 1995-04-17
Project end date: 2005-11-30
2R01CA060675-06A1 (2001): $225151
ADENOVIRUS 243R E1A PROTEIN AND CELLULAR TRANSCRIPTION
Daniel A Engel, Associate Professor
University Of Virginia Charlottesville Box 400195 Charlottesville, Va 229044195
Grant 5R29CA060675-05 from National Cancer Institute IRG: EVR
Abstract: Important insights into the mechanisms of human carcinogenesis have come from the study of DNA tumor viruses. The DNA tumor virus adenovirus provides an ideal system for investigating transcriptional events in cellular transformation. The long-term goal of our research is to understnd the mechanism by which the adenovirus E1A protein alters the normal cellular transcriptional program so as to induce transformation. Here, we focus on the transcriptional regulation of the cellular c-fos gene by the adenovirus 243R E1A protein, and the functional interaction between E1A and the cellular transcriptional machinery. Our previous studies have identified a link between the action of E1A and an important intracellular signling system, the cAMP-dependent protein kinase pathway. This interaction results in the activation of a set of genes that are involved in cellular growth control and transformation. Knowledge gained from studying the effects ofE1A on cellular transcriptional regulation wil lead to better understanding of the molecular events involved in transformation. 1) Identifiction transacting factors involved in the activation of c-fos by E1A and cAMP, A 22 nucleotide "E1A-response element" (ERE) has been identified that mediates activation of c-fos by the 243R E1A protein. The ERE contains binding sites for transcription factors ATF/CREB and YY1. Factors tht bind the ERE will be identified, and the effects of E1A and cAMP on their level and activity will be determined. 2) Structure and function of the ATF/CREB-YY1 complex. YY1 physically interacts with members of the AFT/CREB family of transcription factors. As a prelude to investigating the role of the ATF/CREB-YY1 complex in activation b E1A, structure/function analysis of the ATF/CREB-YY1 interaction will be performed. DNA-binding and transcriptional repression by the complex will also be investigated. 3) The ATF/CREB-YY1 complex as a target ofE1A. E1A can bind to YY1 and alter its DNA-binding properties. The interaction between E1A and YY1, and between E1A and the ATF/CREB-YY1 complex will e studied. Experiments will include structure/function analysis of the E1A-YY1 interaction, as well as in itro and in vivo binding assays. These experiments will lead to a model for the molecular basis of E1a activation of thec-fos gene.
Keywords: Adenoviridae, neoplasm /cancer genetics, protein structure /function, transcription factor, viral carcinogenesis, cAMP response element binding protein, gene induction /repression, genetic regulatory element, genetic transcription, intermolecular interaction, nucleic acid sequence, plasmid, protooncogene, reporter gene, HeLa cell, molecular cloning
Project start date: 1995-04-17
Project end date: 2000-03-31
5R29CA060675-05 (1999): $243
5R29CA060675-04 (1998): $103163
5R29CA060675-03 (1997): $243
YEAST BASED ASSAYS FOR CHEMICAL SCREENS AGAINST SARS-COV TARGETS
Daniel A Engel, Associate Professor
University Of Virginia Charlottesville, Box 400195, Charlottesville, Va 22904-4195
Grant 3R21NS063854-01S1 from Office Of The Director, National Institutes Of Health
Abstract: Human coronaviruses are a diverse group of four antigenically distinct viruses that are important human pathogens that cause upper and lower respiratory tract infections. In young children and the elderly, lower respiratory tract infections can be severe. The recently emerged human coronavirus, SARS-CoV, causes severe pneumonia and death. It is a robust empirical model for identifying pharmacological probes of biological function that can strengthen our understanding of the proteins and pathways involved in establishment of disease. In addition, SARS-CoV is an ideal choice for the identification of broad spectrum antivirals for the treatment of coronavirus induced life threatening disease. In this proposal, we develop and validate novel assays, with plans for high throughput screening efforts during year 2 by the Molecular Libraries Production Centers Network (MLPCN). A yeast based assay will be used for the identification of compounds with activity against the SARS-CoV targets Nsp1 and PLP. Both targets give pronounced phenotypes when expressed in yeast, forming the basis for chemical screens to suppress the phenotypes. Important secondary screens will reveal hits that have anti-SARS-CoV activity, as well as those with broad spectrum activity against human coronaviruses in general. A pilot validation screen will be performed manually with the 2000 member Diversity Set library of compounds. The coronavirus model is robust because molecular clones exist, target genes have been identified that are essential for virus replication, structural information exists for both targets, and robust cell culture and murine models of severe end stage respiratory disease allow for biological evaluation of hits both in vitro and in vivo. In aim 1, we will optimize the expression and growth-inhibitory phenotypes of the Nsp1 and PLP proteins in yeast, characterize their behavior in 96-well plates, and perform the pilot screen. In aim 2, we will evaluate the antiviral activity of hits from the screen against recombinant SARS-CoV and other human coronaviruses encoding reporter genes. The ultimate goal of this proposal is to develop a rational, high throughput yeast-based screen that identifies small molecule inhibitors that target novel viral genes. The impact is high because our studies will develop a new high throughput paradigm to identify novel pharmaceuticals that will be used as molecular probes of coronavirus function. Equally important is that candidate broad spectrum antivirals against the target genes encoded within any microbial pathogen will also be identified. Experienced investigators at the University of Virginia and the University of North Carolina at Chapel Hill propose to develop new ways to discover chemical compounds ("drugs") that can be used to study the biology of the Severe Acute Respiratory Syndrome (SARS) coronavirus, called SARS-CoV. The budding yeast Saccharomyces cerevisiae will be used as a living test tube to measure the effects of specific SARS-CoV proteins on growth. Then, individual chemical compounds will be used to determine which compounds can reverse these effects. The idea here is that compounds that can reverse the effects of SARS-CoV proteins in yeast will also be able to reverse their effects in the human body during a SARS infection. We hypothesize that we can learn about the biology of SARS-CoV by identifying which chemical compounds can inhibit it, and then study how they work
Keywords: 0-11 years old; Adenoviridae; Adenoviruses; Aged 65 and Over; Analysis, Data; Antiviral Agents; Antiviral Drugs; Antivirals; Assay; Automation; Behavior; Bioassay; Biochemical; Biologic Assays; Biological; Biological Assay; Biological Function; Biological Process; Biology; Cell Communication and Signaling; Cell Culture Techniques; Cell Function; Cell Growth in Number; Cell Multiplication; Cell Process; Cell Proliferation; Cell Signaling; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular Proliferation; Cessation of life; Chemicals; Child; Child Youth; Children (0-21); Cleaved cell; Clinical Drug Development; Cloning, Molecular; Communicating Junction; Coronavirus; Coronavirus (genus); Data Analyses; Death; Degradation, mRNA; Development; Disease; Disease model; Disorder; Drug Compounding; Drug Delivery; Drug Delivery Systems; Drug Development, Clinical; Drug Preparation; Drug Targeting; Drug Targetings; Drug Testing/Development, Clinical; Drugs; Economics; Elderly; Elderly, over 65; Endomycetales; Esteroproteases; Evaluation; Gap Junctions; Gene Targeting; Generalized Growth; Genes, Reporter; Genes, Viral; Goals; Grippe; Growth; H5N1; H5N1 virus; High Throughput Assay; Hour; Human; Human Figure; Human body; Human, Child; Human, General; IFN; In Vitro; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Integral Membrane Protein; Interferons; Intracellular Communication and Signaling; Intrinsic Membrane Protein; Investigators; Learning; Libraries; Life; Low-resistance Junction; Lower Respiratory Tract Infection; Lung diseases; Mammals, Mice; Man (Taxonomy); Man, Modern; Measurement; Measures; Medication; Methods; Mice; Modeling; Molecular; Molecular Bank; Molecular Cloning; Molecular Probes; Molecular Virology; Monitor; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nexus; Nexus Junction; North Carolina; Optics; Pathogenesis; Pathway interactions; Peptidases; Peptide Domain; Peptide Hydrolases; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Phenotype; Pneumonia; Pneumonitis; Polyproteins; Production; Proteases; Protein Domains; Proteinases; Proteins; Proteolytic Enzymes; Pulmonary Diseases; Pulmonary Disorder; Pulmonary Inflammation; Reading; Recombinants; Recovery; Reporter Genes; Research Design; Research Personnel; Researchers; Respiratory Disease; Respiratory Disorder; Respiratory System Disease; Respiratory System Disorder; S cerevisiae; SARS; Saccharomyces cerevisiae; Saccharomycetales; Severe Acute Respiratory Syndrome; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Staging; Structural Protein; Study Type; Subcellular Process; System; System, LOINC Axis 4; Targetings, Gene; Tertiary Protein Structure; Testing; Tissue Growth; Transmembrane Protein; Tube; United States National Institutes of Health; Universities; Validation; Viral; Viral Activity; Viral Function; Viral Genes; Viral Physiology; Virginia; Virus; Virus Replication; Viruses, General; Work; Yeast, Baker`s; Yeast, Brewer`s; Yeast, Budding; Yeasts; ing; advanced age; base; biological signal transduction; children; cleaved; density; design; designing; disease/disorder; disorder model; drug discovery; drug/agent; elders; experience; flu infection; gene product; geriatric; high throughput screening; human coronavirus; in vivo; influenza infection; inhibitor; inhibitor/antagonist; late life; later life; lung disorder; mRNA Transcript Degradation; member; microbial; novel; older adult; older person; ontogeny; pathogen; pathway; polypeptide; positional cloning; protein expression; respiratory; respiratory virus; reverse genetics; senior citizen; small molecule; small molecule libraries; study design; time use; virus host interaction; virus multiplication; youngster
Project start date: 2008-06-15
Project end date: 2011-02-28
Budget start date: 15-JUN-2008
Budget end date: 28-FEB-2011
PFA/PA: PAR-08-024
3R21NS063854-01S1 (2010): $38500
CHROMATIN TARGETS FOR CANCER THERAPY
Daniel A Engel, Associate Professor
Microbiologyuniversity Of Virginia Charlottesville
box 400195
charlottesville, Va 229044195
Grant 1R01CA087620-01 from National Cancer Institute IRG: ZCA1
Abstract: Applicant´s Description) Expression of the adenovirus ElA oncoprotein in budding yeast has provided a useful model for uncovering novel pathways involved in oncoprotein action. Remarkably, multiprotein complexes (SWI/SNF and HAT complexes) that mediate chromatin remodeling and transcriptional regulation are targeted by EIA, leading to the strong prediction that disruption their human counterparts is important in the development of cancer. Indeed, there is evidence from human systems that the development of cancer is associated with loss or disregulation of genes encoding components of several SWI/SNF and HAT complexes. Given the clear role of "chromatin dynamics" in cellular regulation, and its genetic involvement in oncogenesis, the pathways which control chromatin function may contain useful targets for anti-cancer drug therapy. This proposal seeks to extend previous work on oncogenesis-related pathways in yeast, and to identify novel compounds with anti-cancer therapeutic potential. Yeast strains with defined defects in chromatin remodeling functions will be subjected to high throughput screens of two libraries The "Diversity Set" of approximately 2000 compounds from the National Cancer Institute´s Developmental Therapeutics Program, and a library of approximately 6000 ethanolic botanical extracts available through the Markey Center for Cell Signaling at the University of Virginia. The proven utility of Saccharomyces cerevisiae for illuminating novel oncogenesis-related pathways will allow genetic dissection of the action of novel lead compounds from the drug screens. Lead compounds will be tested further in mammalian cell culture systems to examine their potential as therapeutic agents, and their specific effects on mammalian chromatin dynamics
Keywords: Saccharomyces cerevisiae, antineoplastic, cell line, chromatin, drug discovery /isolation, drug screening /evaluation, plant extract high throughput technology
Project start date: 2000-07-01
Project end date: 2003-06-30
1R01CA087620-01 (2000): $251280
ADENOVIRUS E1A PROTEIN AND THE SWI/SNF COMPLEX
Daniel A Engel, Associate Professor
University Of Virginia Charlottesville Box 400195 Charlottesville, Va 229044195
Grant 5R01CA060675-10 from National Cancer Institute IRG: VR
Abstract: Adapted from the Investigator s ) The adenovirus E1A protein induces imortalization and transformation of cells in culture and is therefore an excellent model for the study of cellular transformation. E1A binds specific cell proteins including the retinoblastoma protein (Rb) and p300/CBP proteins that control transcription, in part, by altering chromatin structure. E1A inhibits the function of the chromatin remodeling complex SWI/SNF, which interacts with Rb protein and possibly p300. Specific aim 1 proposes to define and characterize the mammalian SWI/SNF complex with respect to its role in regulation of transcription. It will be determined how the complex inhibits c-fos expression at the transcriptional level. The structural changes that accompany the inhibition of c-fos gene activity will be characterized, and assays will be developed to measure the physical association of SWI/SNF with specific mammalian promoters in vivo. Studies will characterize the effects of E1A on SWI/SNF processes. Specific aim 2 will use a yeast genetic approach to understand E1A inhibition of the SWI/SNF complex. The yeast proteins that interact with E1A will be identified and their influence on E1A activity will be determined. Similar studies will then be conducted in mammalian cells using the information gained from the yeast system.
Keywords: Adenoviridae, cell growth regulation, protein structure function, transcription factor, virus protein, cAMP response element binding protein, chromatin, fungal genetics, fungal protein, gene induction /repression, nucleic acid sequence, protein protein interaction, protooncogene, molecular cloning, yeast
Project start date: 1995-04-17
Project end date: 2007-11-30
5R01CA060675-10 (2005): $230961
5R01CA060675-09 (2004): $231023
5R01CA060675-08 (2003): $231084
Sponsored Links Excellgen http://Excellgen.com
5R01CA060675-07 (2002): $231142
Novel Tool Compounds For Chromatin Research
Daniel A Engel, Associate Professor
Millipore Corporation 290 Concord Rd Billerica, Ma 018213405
Grant 1R41CA105604-01 from National Cancer Institute IRG: ZRG1
Abstract: A Phase 1 STTR proposal seeks to identify and develop novel compounds that target chromatin regulatory proteins. A yeast-based assay will be used to screen the National Cancer Institute Diversity Set library of small molecules. The assay consists of defined yeast mutants or reporter strains whose viability depends on one of a number of chromatin-regulatory functions. Compounds that specifically target those functions cause growth inhibition of the mutant strain but not the corresponding wild-type. There are three parts to the proposal. In Aim 1, two screens based on novel reporter strains will be carried out with the Diversity Set in order to identify new inhibitors of chromatin function. In Aim 2, a lead compound from a preliminary screen already conducted wilt be characterized in terms of its effect on histone acetyltransferase activity in vitro and in vivo. Aim 3 will be devoted to developing a panel of seven yeast and mammalian recombinant HAT enzymes that will be used to test the specific functions of the compounds derived from the screens. The proposed work will contribute to two underdeveloped areas. First it will provide new and valuable reagents for the study of chromatin regulation. With the exception of the histone deacetylase inhibitors (HDACs), drugs that target specific chromatin-related pathways and activities are not available. Second, the preliminary data presented here shows proof-of-concept for the yeast-based technology to rapidly identify chromatin regulation inhibitors. These two areas will be the main thrust of the future development of this project.
Keywords: chromatin, drug discovery /isolation, inhibitor /antagonist, small molecule, technology /technique development, acyltransferase, enzyme activity, enzyme inhibitor, reagent /indicator, recombinant protein, chemical registry /resource, genetic manipulation, genetic screening, yeast
Project start date: 2004-08-01
Project end date: 2007-07-31
1R41CA105604-01 (2004): $207596
HIGH THROUGHPUT SCREEN FOR INHIBITORS OF INFLUENZA NS1 PROTEIN FUNCTION
Daniel A Engel, Associate Professor
University Of Virginia Charlottesville, Box 400195, Charlottesville, Va 22904-4195
Grant 1R03MH085680-01 from Roadmap Initiative, Office Of The Director
Abstract: A high-throughput screen is proposed for the identification of inhibitors of the influenza NS1 protein. Influenza is a world-wide public health problem and emerging forms of the virus have the potential to cause a pandemic of equal or greater magnitude to the outbreaks recorded in 1918, 1957 or 1968. Vaccine development is proceeding and there also exist two classes of anti-influenza compounds. However these therapeutic modalities are neither fully effective nor widely enough available to fulfill global needs. In addition their potential usefulness against newly emergent strains is not known. Efforts are needed to develop novel agents against influenza virus, including broad-spectrum agents. Identification of small molecules that inhibit NS1 function either directly or by interfering with specific cellular pathways may be a key to increasing our defense against the virus. A yeast-based assay for NS1 function will be used to screen for novel inhibitors. NS1 induces a pronounced slow-growth phenotype that can be specifically suppressed by small molecule inhibitors. The growth assay has been converted to a 96 well format and it has been shown to be of high quality. A small scale screen of 2000 compounds from the NCI Diversity Set identified several inhibitors of NS1 function that also inhibit influenza virus replication in cell culture. The inhibitors block the ability of NS1 to prevent activation of the interferon response. Some of them also reverse the ability of NS1 to interfere with nuclear-to- cytoplasmic transport of cellular RNA. The high-throughput screen proposed here is expected to identify compounds of higher potency and greater structural diversity than those identified from the small scale screen. This will shed light on the mechanisms of NS1 function and provide starting points for the development of clinically useful agents. Influenza is a world-wide public health problem of major proportions. The likelihood of a devastating influenza pandemic during this century makes it essential to discover new drugs to combat the disease. The proposed high throughput screen for small molecule inhibitors of the NS1 protein from influenza virus will explore the possibility that this protein can be used as a target for clinically useful, broad spectrum therapeutics against influenza virus
Keywords: 5`-Adenylic acid, homopolymer; Assay; Automation; BPTP3; Bioassay; Biologic Assays; Biological; Biological Assay; Blotting, Western; CFC; Cell Function; Cell Process; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Chemistry, Pharmaceutical; Class; Clinical; Clinical Drug Development; Cultured Cells; Data; Development; Disease; Disease Outbreaks; Disorder; Drug Delivery; Drug Delivery Systems; Drug Development, Clinical; Drug Targeting; Drug Targetings; Drug Testing/Development, Clinical; Drugs; Economics; Endomycetales; Gene Expression; Gene Products, RNA; Gene Transcription; Generalized Growth; Genetic Transcription; Goals; Grippe; Growth; H5N1; H5N1 virus; High Throughput Assay; Human; Human Resources; Human, General; INS1 protein, Orthomyxoviridae; INS1 protein, influenza virus; IVNS1 protein, influenza virus; Immune response; In Situ; Influenza; Influenza A Virus, H5N1 Subtype; Influenza Virus; Interferon Activation; Lead; Light; Man (Taxonomy); Man, Modern; Manpower; Measurement; Medication; Medicinal Chemistry; Messenger RNA; Methods; Modality; Molecular; NS1; NS1 protein, influenza virus; Nuclear; Optics; Outbreaks; PCR; PTP-1D; PTP2C; PTPN11; PTPN11 gene; Pathway interactions; Pb element; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Photoradiation; Poly A; Poly(rA); Polymerase Chain Reaction; Proteins; Public Health; RNA; RNA Expression; RNA, Messenger; RNA, Non-Polyadenylated; Reading; Recovery; Ribonucleic Acid; S cerevisiae; SARS Virus; SARS coronavirus; SARS-Associated Coronavirus; SARS-CoV; SARS-Related Coronavirus; SCHED; SH-PTP2; SH-PTP3; SHP-2; SHP2; Saccharomyces cerevisiae; Saccharomycetales; Schedule; Screening Result; Screening procedure; Severe Acute Respiratory Syndrome Virus; Signal Pathway; Structure; Subcellular Process; Surface; Testing; Therapeutic; Tissue Growth; Toxic effect; Toxicities; Transcript; Transcription; Transcription, Genetic; Urbani SARS-Associated Coronavirus; Viral; Viral Activity; Viral Function; Viral Physiology; Virus; Virus Replication; Viruses, General; Western Blotting; Western Blottings; Western Immunoblotting; Work; Yeast, Baker`s; Yeast, Brewer`s; Yeast, Budding; Yeasts; anti-flu; anti-influenza; antiflu; base; concept; density; design; designing; desire; disease/disorder; drug/agent; flu infection; gene product; heavy metal Pb; heavy metal lead; high throughput screening; host response; immunoresponse; influenza infection; influenza virus INS1 protein; influenzavirus; influenzavirus (unspecified); inhibitor; inhibitor/antagonist; insight; mRNA; member; novel; ontogeny; pandemic; pandemic disease; pandemic flu; pandemic influenza; pathogen; pathway; personnel; polyadenylate; prevent; preventing; protein blotting; protein function; public health medicine (field); respiratory; respiratory virus; response; screening; screenings; small molecule; vaccine development; virus multiplication
Relevance: Influenza is a world-wide public health problem of major proportions. The likelihood of a devastating influenza pandemic during this century makes it essential to discover new drugs to combat the disease. The proposed high throughput screen for small molecule inhibitors of the NS1 protein from influenza virus will explore the possibility that this protein can be used as a target for clinically useful, broad spectrum therapeutics against influenza virus
Project start date: 2008-09-30
Project end date: 2010-08-31
Budget start date: 30-SEP-2008
Budget end date: 31-AUG-2010
PFA/PA: PAR-08-035
1R03MH085680-01 (2008): $0
ADENOVIRUS 243R E1A PROTEIN AND CELLULAR TRANSCRIPTION
Daniel A Engel, Associate Professor
Microbiologyuniversity Of Virginia Charlottesville
box 400195
charlottesville, Va 229044195
Grant 5R29CA060675-02 from National Cancer Institute IRG: EVR
Project start date: 1995-04-17
Project end date: 2000-03-31
5R29CA060675-02 (1996): $243