Broad spectrum antivirals targeting envelope proteolysis and viral uncoating

描述（由申请人提供）：自20世纪80年代人类免疫缺陷病毒（HIV）出现以来，人们一直认为，对偏远自然资源的勘探和开发以及世界旅行的增加将导致新的和危险的病毒病原体的进一步流行。丝状病毒、严重急性呼吸道综合征-冠状病毒（SARS-CoV）和副粘病毒属的亨尼帕病毒都是此类病原体的实例。幸运的是，所有这些都未能证明成为真正流行病所需的传播性或动物宿主。然而，新病毒的出现是有规律的，生物武器化增加了现有病毒被改变以增强其致病性或传播性的威胁。目前，几乎没有什么防御措施可以用来治疗各种病毒，特别是那些没有特征的病毒。因此，一系列具有重叠治疗适应症的抗病毒药物将大大有助于对新的或不断变化的大流行威胁作出快速反应。其中一种方法是针对许多病毒利用的共同宿主机制来产生一小组此类药物。我们建议开发一种这样的靶点，即参与病毒糖蛋白加工的宿主细胞蛋白酶抑制剂。病毒糖蛋白和系统差异很大。然而，我们和其他人已经证明，来自不同家族的一整类病毒，包括埃博拉病毒和尼帕病毒，都利用一类单一的宿主因子，内体组织蛋白酶，可以被单独的抑制剂靶向。我们开发的化合物将对NIAID A类优先病原体埃博拉病毒和马尔堡病毒、C类病原体SARS-CoV以及病毒性出血热病毒尼帕和亨德拉具有活性。此外，所述化合物将具有针对另外的人冠状病毒如229 E和呼肠孤病毒的广泛活性。最后，这些化合物很可能对许多编码它们自己的半胱氨酸蛋白酶版本的寄生虫感染有活性。尽管这些病毒有可能成为流行病病原体或被用作生物武器，但对它们都没有有效的治疗剂。蛋白酶抑制剂库的初步筛选已经产生了有前途的先导化合物，其中之一正在由我们的财团成员开发作为南美锥虫病的治疗剂。我们建议对这些化合物进行精制，以增加其药物样特性并优化其对靶病毒的活性。我们最初的先导化合物K777的物理、生物化学和药物性质将通过迭代药物化学进行优化，以生产用于体外测试的面板。 在确定进一步发展的适当候选人之前，将挑选最佳候选人进行进一步改进。我们将进行逃逸突变体选择，以确定病毒如何容易地从这些药物中逃逸以及以何种形式逃逸。总之，我们希望开发一种新型的抑制剂，靶向一系列不同的新兴病毒所需的特定宿主细胞因子，其中许多是潜在的生物武器威胁。

DESCRIPTION (provided by applicant): Since the emergence of human immunodeficiency virus (HIV) in the 1980s it has been assumed that exploration and exploitation of remote natural resources and increases in world travel would result in further pandemics of new and dangerous viral pathogens. Filoviruses, the severe acute respiratory syndrome- coronavirus (Sars-CoV) and the Henipavirus genus of paramyxoviruses are all examples of such agents. Fortunately all have failed to demonstrate the transmissibility or animal reservoirs required to become true pandemics. However, new viruses emerge with regularity and bioweaponization provides the added threat of existing viruses being altered to enhance their pathogenicity or transmissibility. Currently little defense exists in terms of drugs that can be used to treat a wide range of viruses especially uncharacterized ones. Thus, rapid responses to new or changing pandemic threats would be greatly helped by an arsenal of antiviral drugs with overlapping therapeutic indications. One method of doing that is to target common host mechanisms utilized by many viruses to produce a small panel of such drugs. We propose to develop one such target, inhibitors of host cell proteases involved in the processing of viral glycoproteins. Viral glycoproteins and systems vary widely. However, we and others have demonstrated that a whole class of viruses from different families, including Ebola virus and Nipah, all utilize a single class of host factor, endosomal cathepsins, that can be targeted by individual inhibitors. The compounds we develop will be active against the NIAID category A priority pathogens Ebola virus and Marburg virus, and the category C agent SARS-CoV as well as the viral hemorrhagic fever viruses Nipah and Hendra. In addition, the compounds will have broad activity against additional human coronaviruses such as 229E, and reoviruses. Finally, these compounds may well be active against a number of parasitic infections that encode their own versions of cysteine proteases. No effective therapeutic agents exist for any of these viruses, despite their potential to emerge as epidemic pathogens or be utilized as bioweapons. Initial screens of protease inhibitor libraries have yielded promising lead compounds, one of which is being developed by members of our consortium as a therapeutic agent for Chagas disease. We propose to refine these compounds in order to increase their drug-like properties and optimize their activity against the target viruses. The physical, biochemical, and drug-like properties of our initial lead compound, K777, will be optimized via reiterative medicinal chemistry to produce panels for in vitro testing. The best candidates will be selected for further refinement until appropriate candidates for further development are determined. We will perform escape mutant selection to determine how easily virus escapes from these drugs and in what form. In summary, we hope to develop a novel class of inhibitors targeting a specific host cell factor required by a range of different emerging viruses, many of which are potential bioweapon threats.