Inhibitors of poxvirus enzymes as novel drugs

痘病毒酶抑制剂作为新药

• 批准号: 7019977
• 负责人: Esteban Edward Mena
• 金额: $ 83.9万
• 依托单位: LIFEPHARMS, INC.
• 依托单位国家: 美国
• 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/7019977
• 关键词: Basidiomycetes; Poxviridae; Poxviridae disease; RNA biosynthesis; X ray crystallography; antiviral agents; biotechnology; bioterrorism /chemical warfare; biotherapeutic agent; chemoprevention; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; enzyme inhibitors; genetic transcription; host organism interaction; mass spectrometry; messenger RNA; microorganism disease chemotherapy; nuclear magnetic resonance spectroscopy; plant extracts; virion; virus RNA; virus protein; virus replication

EXCEED THE SPACE PROVIDED. 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.

超过提供的空间。 考虑到天花的未宣布的股票 可以用作生物越野武器。而根除天花是预防性的胜利 免疫，天花的治疗从未超出支持疗法。对他人的治疗 人类的痘病毒感染（软体动物contagiosum，monkeypox和免疫并发症与并发症 离发病）也是非特异性或不存在的。人类蒙基毒感染的爆发 2003年美国中西部强调了RE的风险，人类痘病毒疾病的出现。 我们的目标是通过阻止这种方法来鉴定天花的治疗和化学预防药物的新药物 病毒mRNA的转录和上限。我们将筛选Lifepharms独特而专有的图书馆 来自> 13,000次野生蘑菇的提取物，以发现针对针对的痘病毒复制的新抑制剂 mRNA转录设备包装在感染性病毒座的核心内。体外转录 普遍接受透化病毒体的反应，以忠实地概括病毒的早期过程 mRNA生物发生在宿主细胞中发生。通过在体外筛查以抑制mRNA合成和 通过透化病毒体加工，我们希望确定阻塞一个或多个的候选抗病毒药 负责转录和封盖痘病毒早期mRNA的关键病毒酶。这个策略 初级筛查比屏幕比单个病毒蛋白具有关键优势，因为：（i）选择 对于能够在病毒座芯内访问靶的化合物； （ii）它包含多个 单个测定平台内的潜在酶促靶标。目标包括：（i）DNA依赖性RNA 聚合酶； （ii）ETF（早期转录因子），一种DNA依赖性ATPase； （iii）上限酶RNA 三磷酸酶，RNA瓜尼甘尼转移酶和RNA鸟嘌呤-N7甲基转移酶； （iv）nph1，转录 具有DNA依赖性ATPase活性的伸长/终止因子； （v）NPH2，RNA解旋酶； （vi） DNA拓扑异构酶。这些痘病毒酶是杰出的药物靶标和特定抑制剂 酶将为药物开发提供铅化合物，以及用于痘病毒基础研究的关键工具 复制。 尽管真菌天然产品为药理学和药物发现做出了重大贡献，但 仅筛选了所有真菌物种中的一小部分以生物活性化合物。 Lifepharms的图书馆 包含物种多样性几乎等同于先前检查的所有真菌物种。药物发现 在这里的项目大纲合并了真菌生态和自然的Lifepharms，Inc。的互补专业知识 产品提取物的获取，斯图尔特·舒曼（Stewart Shuman）博士在痘病毒酶学和分子生物学中 天然产品研究三角研究所DRU 9发现和药物化学。