Novel Countermeasures to Hemorrhagic Fever Viruses

出血热病毒的新对策

• 批准号: 6562363
• 负责人: Stanley J Watowich
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6562363
• 关键词: Rift Valley fever virus; antiviral agents; biotechnology; bioterrorism /chemical warfare; drug discovery /isolation; hemorrhagic fever; laboratory mouse; molecular cloning; proteomics; recombinant proteins; tissue /cell culture

DESCRIPTION (provided by applicant): Relevance. "Category A" hemorrhagic fever viruses (HFVs), such as Rift Valley fever virus (RVFV), have been under active development for use as BWT agents. Despite extensive effort, no effective medical countermeasures are currently available to combat these threats. Thus, the ability to rapidly generate anti-HFV therapeutics is essential to protect U.S. civilians and Forces, thereby preventing potentially devastating casualties associated with HFV infections. Background. Since current approaches to developing antiviral compounds are extremely costly and time-consuming, but rarely successful, we have developed a revolutionary technology to rapidly generate therapeutics to cytolytic pathogens. Objectives. Our pathogen-selected anti-pathogen technology utilizes diverse (i.e., 10e8) cell-resident combinatorial protein libraries (termed adaptein libraries). We propose to screen these libraries to identify novel broad-spectrum therapeutics that protect cells from challenge with "Category A" HFVs. These therapeutics are designed for use before or after exposure to BWT agents to prevent civilian and military casualties. Study design. To successfully accomplish this innovative project, we have assembled a multi-disciplinary team of expert virologists, microbiologists and structural biologists. Complex adaptein libraries have been integrated into mammalian cells, such that each cell expresses a unique member of the adaptein library. We will challenge these heterogeneous cell populations with RVFV. Cells that survive virus challenge will be selected, cloned, and the protective adaptein responsible for antiviral activity identified by nested-PCR sequencing. Purified cell-permeant variants of each protective adaptein will be developed as therapeutic agents, and the efficacy of these adapteins to protect cells and animals from RVFV will be determined from dose-response studies. During project year 2, our new BSL-4 facility will be available to apply our strategy to other HFVs, and thus test the efficacy of our adapteins against these viruses. In this manner, compounds that provide broad protection against different HFVs will be generated. A significant strength of our technology is that it eliminates the a priori assumptions inherent within target-based or computational drug discovery methods, ultimately allowing our technology to discover novel therapeutics to BWT or emergent pathogens without the need for detailed pathogen characterization.

描述（由申请人提供）：相关性。“A类”出血热病毒（hfv），如裂谷热病毒（RVFV），一直在积极开发中，以用作BWT病原体。尽管作出了广泛的努力，但目前尚无有效的医疗对策来对付这些威胁。因此，快速生产抗HFV治疗药物的能力对于保护美国平民和部队至关重要，从而防止与HFV感染相关的潜在毁灭性伤亡。