Broad spectrum antivirals targeting envelope proteolysis and viral uncoating

说明(申请人提供)：自1980年代人类免疫缺陷病毒(艾滋病毒)出现以来，人们一直认为，对偏远自然资源的勘探和开采以及世界旅行的增加将导致新的危险病毒病原体的进一步流行。丝状病毒、严重急性呼吸综合征冠状病毒(SARS-CoV)和副粘病毒的HenipaVirus属都是这种病原体的例子。幸运的是，所有这些都未能证明成为真正的大流行所需的传播性或动物宿主。然而，新病毒的出现是有规律的，生物电离化提供了现有病毒被改变以增强其致病性或传播性的额外威胁。目前，就可用于治疗各种病毒，特别是未确定特征的病毒的药物而言，几乎没有什么防御措施。因此，对新的或不断变化的大流行威胁的快速反应将大大有助于具有重叠治疗适应症的抗病毒药物的武器库。要做到这一点，一种方法是针对许多病毒利用的常见宿主机制，以生产一小部分此类药物。我们建议开发一个这样的靶点，参与病毒糖蛋白加工的宿主细胞蛋白水解酶的抑制剂。病毒糖蛋白和糖蛋白系统差异很大。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Nipah，都利用一种单一的宿主因子，即内体组织蛋白，可以被个别抑制剂靶向。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冠状病毒以及病毒性出血热病毒Nipah和Hendra具有活性。此外，这些化合物还将对229E和呼肠孤病毒等其他人类冠状病毒具有广泛的活性。最后，这些化合物很可能对一些寄生虫感染有效，这些寄生虫感染编码它们自己版本的半胱氨酸蛋白酶。这些病毒中的任何一种都没有有效的治疗剂，尽管它们有可能成为流行病原体或被用作生物武器。对蛋白酶抑制剂文库的初步筛选已经产生了有希望的先导化合物，其中一种正在由我们的财团成员开发，作为恰加斯病的治疗剂。我们建议对这些化合物进行精制，以增加它们的类药物性质，并优化它们对目标病毒的活性。我们最初的先导化合物K777的物理、生化和类药物性能将通过反复药物化学进行优化，以生产用于体外测试的面板。 将挑选最好的候选人进行进一步完善，直到确定适合进一步发展的候选人。我们将进行逃逸突变体选择，以确定病毒从这些药物中逃逸的容易程度和形式。综上所述，我们希望开发一类针对一系列不同新兴病毒所需的特定宿主细胞因子的新型抑制剂，其中许多病毒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.