Cell Entry Inhibitors for Sin Nombre Virus

Sin Nombre 病毒的细胞进入抑制剂

基本信息

批准号：
7060771
负责人：
Brian L. Hjelle
金额：
$ 24.8万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2008-02-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Many of the pathogens that have properties that would be desirable to a would-be bioterrorist have been little-studied, in part because they cause a relatively limited toll in morbidity and mortality under natural circumstances. In other cases, such as for the North American hantaviruses, poor and medically underserved minority populations are disproportionately affected, making their toll even less visible. Two minority institutions in New Mexico, the University of New Mexico and New Mexico State University, have nevertheless devoted much attention to research on potential weapons of mass destruction (Sin Nombre virus or SNV, anthrax, tularemia, plague, etc) for years, with funding from at least four federal agencies. The hantavirus research portfolio at UNM, for example, has been funded at least $1 million direct/year essentially since its inception in 1994. The anthrax attacks of 2001 demonstrated the willingness and ability of terrorists to deploy bioweapons, which caused panic and severe economic damage. Countermeasures against WMD must be developed quickly to limit the damage exacted by future attacks. This application represents a concerted attack against SNV, a hantavirus that has killed over 100 Americans, including 26 New Mexicans, since its recognition in 1993. We have assembled an interdisciplinary team that pools its resources and skills in novel ways. We have developed interlocking, highly collaborative and cross-informing projects and cores involving project PIs who are genuine leaders in their fields, including several who have worked together productively in the past. The approaches that we have taken in this application will serve as a model that can be adapted successfully to a variety of pathogens other than hantaviruses. By pioneering new collaborative strategies using the SNV model, we will establish efficient, high-throughput methods that will work well against other agents. The core capabilities we describe herein will include high-throughput screening for antiviral effects of drugs, computer-assisted modeling that will be used to quickly refine and optimize lead compounds, and evaluation of the efficacy of drugs with sophisticated and quantitative animal model testing. The projects include (1) phage display to develop lead compounds that inhibit SNV entry into cells; (2) computational modeling of drugs; (3) development of RNA aptamer inhibitors of replication and/or packaging using SELEX; (4) development of potent human anti-SNV monoclonal antibodies; and (5) development of sophisticated mechanism-of-action assays to speed development of replicative inhibitors of SNV. Animal model, virology and structural analyses cores will each provide multiple projects with critical reagents or perform the molecular modeling services that are needed to improve lead compounds.

描述（由申请人提供）：许多具有生物恐怖主义者所期望的特性的病原体受到了很少的研究，部分原因是它们在自然环境下造成的发病率和死亡率相对有限。在其他情况下，例如北美汉坦病毒，贫困和医疗服务不足的少数群体受到了不成比例的影响，使他们的损失更加明显。多年来，新墨西哥州大学，新墨西哥大学和新墨西哥州立大学的两个少数族裔机构一直致力于研究潜在的大规模杀伤性武器（Sin nombre病毒或SNV，炭疽病，Tularemia，Plague等）多年来，并拥有至少四个联邦机构的资金。例如，自1994年成立以来，UNM的Hantavirus Research Portfolio在INM的hantavirus Research组合本质上至少是直接每年的100万美元。2001年的炭疽袭击表明，恐怖分子愿意和能力部署生物武器，这造成了恐慌和严重的经济损害。必须迅速开发针对WMD的对策，以限制未来攻击所造成的损害。该申请代表了针对SNV的一致攻击，SNV是一项自1993年认可以来，炸死了100多名美国人，其中包括26个新墨西哥州。我们已经开发了涉及PIS项目的互锁，高度协作和交叉信息的项目和核心，这些项目是他们领域的真正领导者，其中包括一些过去的有效工作。我们在此应用程序中采取的方法将作为一个模型，可以成功地适应汉坦病毒以外的各种病原体。通过使用SNV模型开创新的协作策略，我们将建立有效，高通量的方法，可以很好地与其他代理商对抗。我们在本文描述的核心能力将包括对药物的抗病毒作用的高通量筛查，计算机辅助建模，这些建模将用于快速改进和优化铅化合物，并评估具有复杂和定量动物模型测试的药物的疗效。这些项目包括（1）噬菌体显示，以开发限制SNV进入细胞的铅化合物；（2）药物的计算建模；（3）使用SELEX的复制和/或包装的RNA适体抑制剂的发展；（4）发展有效的人类抗SNV单克隆抗体；（5）开发复杂的行动机理测定法，以加快SNV复制抑制剂的发展。动物模型，病毒学和结构分析核心将分别为多个项目提供关键试剂或执行改善铅化合物所需的分子建模服务。