INHIBITION OF INFLUENZA VIRUS NS1 FUNCTION BY SMALL MOLECULES

描述(由申请人提供)：这项建议利用对流感病毒NS1蛋白活性的广泛研究获得的知识，设计出一种战略，将导致发现新的流感病毒候选药物。人们普遍承认，流感大流行的后果可能是毁灭性的，我们没有足够的治疗资源可用。对M2抑制剂的广泛耐药性，以及最近对神经氨酸酶抑制剂的耐药性，使我们迫切需要开发新的和改进的抗流感病毒药物。我们建议使用流感病毒NS1蛋白作为发现下一代抗病毒药物的新靶点。NS1作为先天免疫反应的抑制因子，其作用最终决定了受感染宿主的疾病严重程度。具体地说，NS1阻止干扰素的产生，以应对病毒感染。缺乏NS1的流感病毒不会引起疾病，因为宿主免疫反应(最强大的天然抗病毒药物)可以正常发挥作用并消除病毒。因此，我们推断，抑制干扰素抑制剂NS1的化合物应该具有类似的作用，以防止病毒生长和疾病进展。我们已经开发了一种基于细胞的报告实验来监测NS1的功能，我们将使用它来筛选小分子化合物的文库，并识别那些降低NS1免疫抑制作用的化合物。这些化合物代表了新的流感病毒候选药物，可以进一步评估和开发，以确定其全部潜力。与公共卫生相关：流感病毒导致一种高度传染性的急性呼吸道疾病，每年影响5%-20%的美国人口。人们对FDA批准的两类流感抗病毒药物的耐药性高度关注，因此我们非常需要新的抗病毒药物来治疗和预防流感感染。在这项建议中，我们描述了使用流感NS1蛋白作为寻找下一代流感抗病毒药物的新靶点。

DESCRIPTION (provided by applicant): This proposal uses knowledge gained from extensive research into the activity of the influenza virus NS1 protein, to devise a strategy that will lead to the discovery of new influenza virus drug candidates. It is widely acknowledged that the consequences of an influenza pandemic could be devastating and that we do not have sufficient therapeutic resources available. Widespread resistance to the M2 inhibitors, and most recently to the neuraminidase inhibitors as well, makes it imperative that we develop new and improved antiviral drugs against influenza virus. We propose to use the influenza virus NS1 protein as a novel target for the discovery of the next generation of antiviral drugs. NS1 functions as an inhibitor of the innate immune response and its actions ultimately determine disease severity in the infected host. Specifically, NS1 prevents the production of interferon in response to virus infection. Influenza viruses that lack NS1 do not cause disease as the host immune response (the most powerful natural antiviral) can function normally and eliminate the virus. Thus, we reason that compounds which inhibit the interferon inhibitor, NS1, should work similarly to prevent virus growth and disease progression. We have developed a cell-based reporter assay for monitoring NS1 function which we will use to screen libraries of small molecular weight compounds and identify those that reduce the immune-suppressing actions of NS1. Such compounds represent new influenza virus drug candidates that can be further evaluated and developed to determine their full potential. PUBLIC HEALTH RELEVANCE: Influenza viruses cause a highly contagious, acute respiratory disease that affects 5-20% of the US population each year. There is heightened concern regarding resistance to both of the two classes of FDA-approved influenza antiviral drugs and therefore we are in great need of new antiviral drugs to treat and prevent influenza infections. In this proposal we describe using the influenza NS1 protein as a new target for finding the next generation of influenza antiviral drugs.