Broad spectrum antivirals targeting envelope proteolysis and viral uncoating

针对包膜蛋白水解和病毒脱衣的广谱抗病毒药物

基本信息

批准号：
8566642
负责人：
GRAHAM SIMMONS
金额：
$ 27.75万
依托单位：
VITALANT
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8566642
关键词：
Africa Animals Antiviral Agents Asians Australia Biochemical Biological Assay Biological Warfare Capsid Categories Cathepsin L Cathepsins Cathepsins B Cells Chagas Disease Chemicals Chimera organism Coronavirus Cysteine Protease Cysteine Proteinase Inhibitors Development Disease Outbreaks Documentation Ebola virus Epidemic Equus caballus Escape Mutant Family Family suidae Filovirus Frankfurt-Marburg Syndrome Virus Glycoproteins Goals HIV Hendra Virus Henipavirus Individual Integration Host Factors Investigation Lead Libraries Measures Mediating Metabolic Methods National Institute of Allergy and Infectious Disease Natural Increases Natural Resources Nipah Virus Paramyxovirus Parasitic infection Pathogenicity Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Process Property Protease Inhibitor Proteolysis Reliance Reovirus Resistance development Reston SARS coronavirus Saudi Arabia Severe Acute Respiratory Syndrome Solubility Structure-Activity Relationship System Testing Therapeutic Therapeutic Agents Toxic effect Travel Vaccines Variant Vesicular stomatitis Indiana virus Viral Viral Hemorrhagic Fevers Virus Virus-like particle analog combat design hemorrhagic fever virus human coronavirus in vitro activity in vitro testing in vivo inhibitor/antagonist member novel pandemic disease passive antibodies pathogen public health relevance respiratory response

项目摘要

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.

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）和副粘病毒亨尼帕病毒属都是此类病原体的例子。幸运的是，所有这些都未能证明成为真正的流行病所需的传播性或动物宿主。然而，新病毒会定期出现，而生物武器化则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，可用于治疗多种病毒（尤其是未知病毒）的药物几乎没有防御措施。因此，具有重叠治疗适应症的抗病毒药物库将极大地帮助快速应对新的或不断变化的大流行威胁。一种方法是针对许多病毒利用的常见宿主机制来生产一小部分此类药物。我们建议开发一种这样的靶标，即参与病毒糖蛋白加工的宿主细胞蛋白酶的抑制剂。病毒糖蛋白和系统差异很大。然而，我们和其他人已经证明，来自不同科的一整类病毒，包括埃博拉病毒和尼帕病毒，都利用一类宿主因子，即内体组织蛋白酶，可以被单个抑制剂靶向。我们开发的化合物将有效对抗 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病毒和亨德拉病毒。此外，这些化合物对其他人类冠状病毒（如 229E 和呼肠孤病毒）具有广泛的活性。最后，这些化合物很可能对许多编码其自身版本的半胱氨酸蛋白酶的寄生虫感染具有活性。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，但目前还没有针对这些病毒的有效治疗剂。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，我们联盟的成员正在开发其中一种作为恰加斯病的治疗剂。我们建议对这些化合物进行精炼，以增强其药物特性并优化其针对目标病毒的活性。我们最初的先导化合物 K777 的物理、生化和类药物特性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。将选择最佳候选人进行进一步细化，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难易程度以及以何种形式逃逸。总之，我们希望开发一类新型抑制剂，针对一系列不同新兴病毒所需的特定宿主细胞因子，其中许多病毒是潜在的生物武器威胁。