Cell Entry Inhibitors for Sin Nombre Virus

描述(由申请人提供)： 许多具有潜在生物恐怖分子所希望的特性的病原体很少被研究，部分原因是它们在自然情况下导致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的影响不成比例，使他们的损失更加不明显。然而，新墨西哥州的两所少数群体机构--新墨西哥大学和新墨西哥州立大学--多年来在至少四个联邦机构的资助下，对可能的大规模毁灭性武器(黑热病病毒、炭疽热、图拉热症、鼠疫等)的研究投入了极大的关注。例如，自1994年成立以来，UNM的汉坦病毒研究组合基本上每年至少直接获得100万美元的资金。2001年的炭疽袭击表明了恐怖分子部署生物武器的意愿和能力，这造成了恐慌和严重的经济损失。必须迅速制定针对大规模杀伤性武器的对策，以限制未来袭击造成的损害。 这款应用程序代表了对SNV的协同攻击，SNV是一种汉坦病毒，自1993年发现以来，已导致100多名美国人死亡，其中包括26名新墨西哥州人。我们已经组建了一个跨学科的团队，以新颖的方式汇集其资源和技能。我们开发了相互关联、高度协作和相互通报的项目和核心，涉及项目绩效指标，他们是各自领域的真正领导者，包括几个在过去一起富有成效地合作的项目绩效指标。我们在这项申请中采取的方法将作为一种模型，可以成功地适应汉坦病毒以外的各种病原体。通过使用SNV模型开创新的协作战略，我们将建立高效、高吞吐量的方法，这些方法将很好地对抗其他代理。 我们在这里描述的核心能力将包括高通量筛选药物的抗病毒效果，用于快速提炼和优化先导化合物的计算机辅助建模，以及通过复杂和定量的动物模型测试评估药物的疗效。这些项目包括(1)噬菌体展示，以开发抑制新城疫病毒进入细胞的先导化合物；(2)药物的计算机模拟；(3)利用SELEX开发复制和/或包装的RNA适体抑制剂；(4)开发有效的人抗新城疫病毒单抗；以及(5)开发复杂的作用机制分析，以加快新城疫病毒复制抑制剂的开发。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进先导化合物所需的分子建模服务。

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.