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：
8662196
负责人：
GRAHAM SIMMONS
金额：
$ 22.15万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662196
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）：自从1980年代人类免疫缺陷病毒（HIV）出现以来，人们已经假定，探索和剥削偏远的自然资源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大流行。铁病毒，严重的急性呼吸道综合征 - 冠状病毒（SARS-COV）和paramyxovirus的HENIPAVIRUS属都是此类药物的例子。幸运的是，所有人都没有证明成为真正的大流行所需的可传播性或动物储藏。然而，新的病毒具有规律性和生物温波化，这为现有病毒的额外威胁带来了额外的威胁，以增强其致病性或可传播性。目前，在可用于治疗广泛的病毒尤其是未表征的药物方面，几乎没有防御能力。因此，对新的或不断变化的大流行威胁的快速反应将通过具有重叠的治疗迹象的抗病毒药物的武器库有很大帮助。一种方法是靶向许多病毒使用的常见宿主机制来生产一小部分此类药物。我们建议开发一种涉及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。但是，我们和其他人已经证明，包括埃博拉病毒和尼帕在内的不同家庭的整个病毒都利用单个宿主因子，内体组织蛋白酶，可以由个别抑制剂靶向。我们开发的化合物将对NIAID类别具有优先病原体的埃博拉病毒和Marburg病毒，以及C类C剂SARS-COV以及病毒出血热病毒Nipah和Hendra。此外，这些化合物将针对其他人类冠状病毒（例如229E和蠕虫病毒）具有广泛的活性。最后，这些化合物很可能与许多编码自己的半胱氨酸蛋白酶版本的寄生虫感染相对活跃。这些病毒中的任何一种都没有有效的治疗剂，尽管它们有可能作为流行病病原体或被用作生物群。蛋白酶抑制剂文库的初始筛选产生了有希望的铅化合物，其中一种是由我们的财团成员作为chagas病的治疗剂开发的。我们建议改善这些化合物，以提高其类似药物的特性并优化其针对靶病毒的活性。我们初始铅化合物K777的物理，生化和类似药物样性能将通过重复性药物化学进行优化，以生产用于体外测试的面板。最好的候选人将被选择进一步完善，直到确定适当的候选人。我们将执行逃生突变体的选择，以确定病毒从这些药物和哪种形式中逃脱。总而言之，我们希望开发出针对各种不同新兴病毒所需的特定宿主细胞因子的新型抑制剂，其中许多是潜在的生物武器威胁。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interferon-Induced Transmembrane Protein-Mediated Inhibition of Host Cell Entry of Ebolaviruses.

DOI：
10.1093/infdis/jiv255
发表时间：
2015-10-01
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Wrensch F;Karsten CB;Gnirß K;Hoffmann M;Lu K;Takada A;Winkler M;Simmons G;Pöhlmann S
通讯作者：
Pöhlmann S