Small molecule inhibitors for influenza treatment

用于流感治疗的小分子抑制剂

基本信息

批准号：
9409086
负责人：
Cyrille Gineste
金额：
$ 30万
依托单位：
ALEXANDER BIODISCOVERIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9409086
关键词：
Accounting Adamantane Address Affect Antiviral Agents Attention Binding Biological Assay Birds Cell Culture Techniques Cell Nucleus Cells Cessation of life Chemicals Clinical Dangerousness Development Drug Targeting Drug resistance Ensure Escape Mutant Family suidae Feasibility Studies Future Genetic Genetic Transcription Genome Hospitalization Human In Vitro Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Influenza Therapeutic Lead M2 protein Morbidity - disease rate Neuraminidase inhibitor Nuclear Nucleoproteins Oseltamivir Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Play Population Production Property Public Health RNA RNA Viruses RNA replication Readiness Research Resistance Role Series Technology Testing Time United States Vaccines Validation Variant Viral Virus Yeasts analog anti-influenza base combat combinatorial cytotoxicity drug discovery efficacy study fitness improved in vivo influenza epidemic influenza virus vaccine influenzavirus inhibitor/antagonist innovation lead series mortality novel novel therapeutics pandemic disease pandemic influenza phase 2 study prevent resistant strain scaffold seasonal influenza small molecule inhibitor therapeutic target

项目摘要

Influenza is a continuing worldwide public health problem associated with significant morbidity and mortality. Seasonal influenza epidemics affect about 10% of the world's population, and annual estimates of mortality range from 250,000 – 500,000 deaths. Due to constant antigenic drift, the approved seasonal influenza vaccine is variably effective from year to year, and a universal vaccine is still a long way off. Two classes of antivirals have been developed, the adamantanes, which target the viral M2 protein, and the viral neuraminidase (NA) inhibitors. However, drug resistance has abolished clinical adamantane use, and there is a growing problem of resistance to oseltamivir, the most widely prescribed of the NA inhibitors. Because of drug resistance issues, lack of a universal vaccine, and the threat of future pandemics, there is a clear and pressing need for development of novel anti-influenza therapeutics. Influenza virus is an enveloped, negative strand RNA virus whose genome is copied in the nucleus of infected cells. The viral nucleoprotein NP plays critical roles in RNA packaging, transcription of the genome to the positive sense species, and RNA replication to negative sense genomes for new virus production. For these reasons NP is an attractive drug target. Alexander BioDiscoveries, LLC has identified novel, specific, potent inhibitors of NP using an innovative, yeast- based antiviral drug discovery technology. These inhibitors bind directly to NP and also prevent its accumulation in the nucleus of infected cells, accounting for its potent antiviral activity. A one-year Phase I feasibility study is proposed to establish robust SAR that will lay the groundwork for a future Phase II study directed at lead optimization, PK and in vivo efficacy studies. In Specific Aim 1, a comprehensive medicinal chemistry approach will be undertaken to improve potency, establish SAR and ensure drug-like properties. Two distinct starting points have been chosen, each based on compounds with excellent antiviral activity in cell culture and minimal cytotoxicity. Combinatorial and discrete syntheses will be conducted to generate numerous analogs for in vitro binding studies and antiviral testing. For Specific Aim 2, a combination of antiviral, in vitro binding, cytotoxicity, and NP nuclear localization assays will be used to assess activity of analogs generated in Aim 1. Selected compounds will also be compared with oseltamivir and in addition be used in combination with oseltamivir. Broad-spectrum activity will be addressed using a variety of recent H1N1 and H3N2 seasonal strains, including oseltamivir-resistant and adamantane-resistant strains. Selected compounds will be used to select viral escape mutants in order to characterize the genetics of drug resistance, if it exists, and the fitness of resistant viral variants.

流感是一个持续存在的全球公共卫生问题，发病率和死亡率很高。季节性流感流行影响世界约 10% 的人口，每年估计死亡率由于持续的抗原漂移，批准的季节性流感导致 250,000 至 500,000 人死亡。疫苗的效果每年都有所不同，距离通用疫苗还有很长的路要走。两类疫苗。已经开发出抗病毒药物，金刚烷（针对病毒 M2 蛋白）和病毒神经氨酸酶 (NA) 抑制剂然而，耐药性已经废除了金刚烷的临床使用。对奥司他韦（最广泛使用的 NA 抑制剂）的耐药性问题日益严重。耐药性问题、缺乏通用疫苗以及未来流行病的威胁，有一个明确且明确的问题迫切需要开发新型抗流感疗法。流感病毒是一种有包膜的阴性病毒。链RNA病毒，其基因组在受感染细胞的细胞核中复制，病毒核蛋白NP发挥作用。在 RNA 包装、基因组转录为正义物种以及 RNA 复制中发挥关键作用出于这些原因，NP 是一个有吸引力的药物靶标。 Alexander BioDiscoveries, LLC 使用创新的酵母菌鉴定了新型、特异、有效的 NP 抑制剂这些抑制剂直接与 NP 结合并阻止其发生。积聚在受感染细胞的细胞核中，解释了其一年期的有效抗病毒活性。提议进行可行性研究，以建立强大的SAR，为未来的第二阶段研究奠定基础针对先导化合物优化、PK 和体内功效研究，具体目标 1 是一项综合性药物研究。将采用化学方法来提高效力、建立 SAR 并确保药物的类似特性。选择了两个不同的起点，每个起点都基于在细胞中具有优异抗病毒活性的化合物将进行组合和离散合成以产生培养物和最小的细胞毒性。用于体外结合研究和抗病毒测试的多种类似物，针对特定目标 2，组合使用。抗病毒、体外结合、细胞毒性和 NP 核定位测定将用于评估目标 1 中生成的类似物。选定的化合物还将与奥司他韦进行比较，此外与奥司他韦联合使用将使用多种最近的 H1N1 药物来解决广谱活性。和 H3N2 季节性菌株，包括奥司他韦耐药菌株和金刚烷耐药菌株。化合物将用于选择病毒逃逸突变体，以表征耐药性的遗传学，如果存在的话，以及耐药病毒变种的适应性。