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Inhibitors of poxvirus enzymes as novel drugs

痘病毒酶抑制剂作为新药

基本信息

批准号：
7373543
负责人：
Esteban Edward Mena
金额：
$ 87.03万
依托单位：
LIFEPHARMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7373543
关键词：
Agaricales Antiviral Agents Ascomycota Basidiomycota Biogenesis Biological Assay Biological Factors Cells Chemoprophylaxis Cultured Cells DNA Topoisomerases DNA biosynthesis DNA-Directed RNA Polymerase DNA-dependent ATPase Disease Disease Outbreaks Drug Compounding Drug Delivery Systems Ecology Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Equipment and supply inventories Genetic Transcription Goals Growth Guanine Human Immunization In Vitro Individual Infection Institutes Lead Libraries Mass Spectrum Analysis Messenger RNA Methodology Methyltransferase Midwestern United States Molecular Biology Molecular Target Molluscum Contagiosum Monkeypox Morphogenesis One-Step dentin bonding system Orthopoxvirus Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Poison Poisoning Poxviridae Poxviridae Infections Process Processed Genes Protein Biosynthesis RNA RNA Helicase RNA triphosphatase Reaction Research Risk Sampling Screening procedure Smallpox Source Structure Supportive care Transcription Elongation Vaccinia virus Viral Viral Proteins Virion Virus Replication X-Ray Crystallography analog base drug development drug discovery fungus inhibitor/antagonist mRNA guanylyltransferase novel particle prophylactic research study termination factor tool transcription factor

项目摘要

Antipoxvirus drug targets are a pressing issue, given the concern that undeclared stocks of smallpox might be used as a bioterror weapon. Whereas the eradication of smallpox was a triumph of prophylactic immunization, the treatment of smallpox never advanced beyond supportive therapy. Treatments for other poxvirus infections of humans (molluscum contagiosum, monkeypox, and complications of immunization with vaccinia virus) are also either nonspecific or nonexistent. The outbreak of human monkeypox infections in the US Midwest in 2003 highlighted the risks of re,emergence of human poxvirus disease. Our goal is to identify novel drugs for the treatment and chemoprophylaxis of smallpox by blocking the transcription and capping of viral mRNAs. We will screen LifePharms' unique and proprietary library of extracts from >13,000 wild mushrooms to discover new inhibitors of poxvirus replication targeted to the mRNA transcription apparatus packaged within the core of the infectious virion. The in vitro transcription reaction of permeabilized virions is generally accepted to faithfully recapitulate the process of viral early mRNA biogenesis as it occurs in the host cell. By screening in vitro for inhibition of mRNA synthesis and processing by permeabilized virions, we expect to identify candidate antivirals that block one or more of the key viral enzymes responsible for transcription and capping of poxvirus early mRNAs. This strategy for primary screening has key advantages over screens against individual viral proteins because: (i) it selects for compounds that are capable of accessing the target within the virion core; and (ii) it embraces multiple potential enzymatic targets within a single assay platform. The targets include: (i) DNA-dependent RNA polymerase; (ii) ETF (early transcription factor), a DNA-dependent ATPase; (iii) the capping enzymes RNA triphosphatase, RNA guanylyltransferase and RNA guanine-N7 methyltransferase; (iv) NPH1, a transcription elongation/termination factor with DNA-dependent ATPase activity; (v) NPH2, an RNA helicase; and (vi) DNA topoisomerase. These poxvirus enzymes are outstanding drug targets and specific inhibitors of these enzymes will provide lead compounds for drug development as well as key tools for basic studies of poxvirus replication. Although fungal natural products has made major contributions to pharmacology and drug discovery, only a fraction of all fungal species have been screened for bioactive compounds. LifePharms' library contains species diversity nearly equivalent to all fungal species examined previously. The drug discovery project outline here merges the complementary expertise of LifePharms, Inc. in fungal ecology and natural product extract acquisition, Dr. Stewart Shuman in poxvirus enzymology and molecular biology, and Research Triangle Institute in natural product dru 9 discovery and medicinal chemistry.

鉴于对未申报的天花库存的担忧，抗痘病毒药物目标是一个紧迫的问题