Novel Antirivals for Hantavirus Pulmonary Syndrome

汉坦病毒肺综合征的新型抗竞争对手

• 批准号: 6561048
• 负责人: JEFFREY B ARTERBURN
• 金额: $ 20.85万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561048
• 关键词: DNA directed RNA polymerase; Hantavirus; Sin Nombre virus; antiviral agents; bioterrorism /chemical warfare; biotherapeutic agent; cell mediated lymphocytolysis test; chemical synthesis; combinatorial chemistry; cytotoxicity; drug design /synthesis /production; emerging infectious disease; enzyme linked immunosorbent assay; guanosine; hemorrhagic fever; immunologic substance development /preparation; peptide library; plaque assay; renal failure; tissue /cell culture; virulence; virus cytopathogenic effect; virus replication

DESCRIPTION (provided by applicant): The long-term objective of this application is to develop effective new antiviral drugs for the treatment of Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) caused by the hantavirus. Viruses in the Hantavirus genus, family Bunyaviridae, are high priority Category A viral hemorrhagic fever agents that poses a risk to national security. To date, more than 20 hantaviruses have been described, half of which cause HFRS or HPS. Approximately 150,000 to 200,000 hospitalized cases of HFRS are reported each year throughout the world, with more than half typically occurring in China. The rest are found throughout other parts of Asia, Europe, Russia and Scandinavia. Mortality rates for HFRS vary from 1%-15%, depending in part on which hantavirus caused the infection. The prototype HFRS-hantavirus, Hantaan virus (HTNV), was isolated in 1976 from the lungs of an infected Korean field mouse (Apodemus agrarius). The Sin Nombre virus, the prototype HPS-hantavirus, was first isolated from New Mexico, and has mortality rates of approximately 40%. No licensed vaccines are available for the prevention of HFRS or HPS, and therapeutic efforts are generally limited to supportive care. Our approach for the development of new hantavirus antiviral drugs is guided by mechanistic biochemistry to design and synthesize a series of novel compounds that target the viral replication and transcription pathways. The Specific Aims of this project are 1) to synthesize combinatorial libraries of antiviral drug candidates; 2) to determine the compounds antiviral activity using cell culture and virion-based assays with SNV and HTNV; 3) to conduct systematic chemical modification and in vitro evaluation of resulting change in antiviral activity profile to develop a quantitative structure activity relationship model (QSAR), that will lead to the development of highly active analogs for therapy.

描述（由申请人提供）：本申请的长期目标是开发有效的新抗病毒药物，用于治疗肾脏综合征（HFRS）和汉塔病毒肺综合征（HPS）（HPS）。汉坦病毒属的病毒是Bunyaviridae家族，是高优先级类别，一种病毒出血性发烧药，对国家安全构成风险。迄今为止，已经描述了20多个汉坦病毒，其中一半引起HFRS或HPS。每年在世界各地报告大约15万至200,000例住院的HFR病例，其中一半以上发生在中国。其余的都在亚洲，欧洲，俄罗斯和斯堪的纳维亚州的其他地区找到。 HFRS的死亡率从1％-15％不等，取决于汉塔病毒引起感染。 1976年，原型HFRS-Hantavirus Hantaan病毒（HTNV）是从感染的韩国野外小鼠（Apodemus agrarius）的肺中分离出来的。 Sin nombre病毒是原型HPS-Hantavirus，首先是从新墨西哥州分离出来的，死亡率约为40％。没有许可的疫苗可用于预防HFRS或HPS，并且治疗工作通常仅限于支持性护理。我们开发新汉塔病毒抗病毒药的方法是由机械生物化学来指导的，以设计和合成一系列针对病毒复制和转录途径的新型化合物。该项目的具体目的是1）综合抗病毒药物候选物的组合文库； 2）使用SNV和HTNV的基于细胞培养和基于病毒粒子的测定确定化合物的抗病毒活性； 3）进行系统的化学修饰和体外评估抗病毒活性谱的变化以开发定量结构活动关系模型（QSAR），这将导致发展高度活性的治疗类似物。