Development of CoV inhibitors against non-enzymatic targets

针对非酶靶标的 CoV 抑制剂的开发

基本信息

批准号：
10514327
负责人：
Adolfo Garcia-Sastre
金额：
$ 512.2万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514327
关键词：
2019-nCoV Amino Acid Substitution Amino Acids Animal Model Animal Testing Antiviral Therapy Attenuated Binding Biochemical Biochemical Genetics Biological Assay Biological Availability Biology Biophysics Cell Line Cells Cellular biology Chemicals Clinic Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Development Elements Enzymes Epithelial Cells Family Formulation Funding Gene Expression Genetic Genetic Transcription HIV Hepatitis C Hepatitis C Therapy Hepatitis C virus Immune response Impairment In Vitro Lead Lung Medicine Nature Oligonucleotides Organoids Pathogenesis Peptide Hydrolases Phase Polymerase Post-Translational Protein Processing Program Development Property Protease Inhibitor Proteins RNA RNA Degradation RNA Sequences RNA replication Research Personnel SARS-CoV-2 genome SARS-CoV-2 inhibitor Sarbecovirus Simplexvirus Site-Directed Mutagenesis Structure Therapeutic Therapeutic Intervention Translations Universities Viral Viral Physiology Viral Proteins Virulence Virus Virus Diseases Virus Inhibitors Virus Replication antiviral drug development base clinical candidate design functional disability improved in silico in vitro activity in vivo inhibitor member novel therapeutics pandemic preparedness prevent small molecule libraries targeted treatment uptake viral RNA virology virus host interaction

项目摘要

SUMMARY The use of viral enzymes as targets for antiviral development has led to many antiviral therapies of use in the clinic. Several viral polymerase and/or protease inhibitors have been developed for HIV, HCV and HSV, among others. Less common is the development of antivirals against viral products with unknown enzymatic properties, although some exceptions include the NS5b inhibitors used for the treatment of HCV infections. As many viral products lack clear enzymatic activities that can be used to develop in vitro screen assays for inhibitors, the use of viral enzymes as targets for therapeutic intervention limits the number of available viral targets. In project 4 – Development of CoV Inhibitors Against Non-Enzymatic Targets of this antiviral development consortium, we explore SARS-CoV-2 targets with unknown enzymatic activities and not covered by the additional SARS-CoV-2 projects of this proposal. We have chosen as targets both a viral protein required for virulence, Nsp1, as well as the viral RNA. Both the viral Nsp1 and the viral RNA have specific unique sequences and structures that distinguish them from host molecules. In aim 1, we combine biochemical, genetic, structural and in silico approaches to identify therapeutic molecules that prevent the inhibition of host responses exerted by Nsp1 in infected cells. In aim 2 we use advanced antisense strategies to target specific conserved functional sequences of the viral RNA involved in replication, transcription and/or translation. In aim 3, we plan to identify molecules that bind and prevent the function of conserved RNA structures that guide viral RNA replication and transcription. For this purpose, we have assembled a team of investigators with ample expertise in the use of RNA-based therapies, virology, cell biology, RNA biology and host-virus interactions. This team interacts closely with the Cores of this consortium to benefit of the structural, ADME and PK expertise, as well as of the antiviral assays, animal models and chemical libraries provided by these Cores. While the Project is mainly in an exploratory phase, several hits that target RNA sequences (Aim 2) or RNA structures (Aim 3), have already been identified and will move forward in the antiviral pipeline of our consortium. For others, like Nsp1, there is enough biochemical and cell biology available information, with many of this information generated by the members of our team, that justifies the proposed screen for Nsp1 inhibitors. Advancement of such classes of inhibitors against unconventional viral targets will open the door for the development of new therapies against other viruses and viral products with unknown enzymatic function, expanding our druggable space for the treatment of viral infections.

概括使用病毒酶作为抗病毒开发的靶标导致了许多抗病毒疗法的使用现已开发出多种针对 HIV、HCV 和 HSV 的病毒聚合酶和/或蛋白酶抑制剂。其他不太常见的是开发针对具有未知酶特性的病毒产品的抗病毒药物，但也有一些例外，包括用于治疗 HCV 感染的 NS5b 抑制剂。产品缺乏可用于开发抑制剂体外筛选分析的明确酶活性，使用病毒酶作为治疗干预的靶点限制了项目 4 中可用病毒靶点的数量。针对该抗病毒开发联盟的非酶目标的 CoV 抑制剂的开发，我们探索具有未知酶活性且未被其他 SARS-CoV-2 覆盖的 SARS-CoV-2 靶标我们选择了毒力所需的病毒蛋白 Nsp1 和 Nsp1 作为目标。病毒 Nsp1 和病毒 RNA 都具有特定的独特序列和结构。将它们与宿主分子区分开来在目标 1 中，我们将生物化学、遗传、结构和计算机结合起来。鉴定可防止 Nsp1 抑制宿主反应的治疗分子的方法在目标 2 中，我们使用先进的反义策略来靶向特定的保守功能序列。在目标 3 中，我们计划识别参与复制、转录和/或翻译的病毒 RNA。结合并阻止指导病毒 RNA 复制和转录的保守 RNA 结构的功能。为此，我们组建了一个研究团队，他们在使用基于 RNA 的技术方面拥有丰富的专业知识。该团队与疗法、病毒学、细胞生物学、RNA 生物学和宿主病毒相互作用密切互动。该联盟的核心受益于结构、ADME 和 PK 专业知识以及抗病毒检测，这些核心提供的动物模型和化学库，而该项目主要处于探索性阶段。阶段，已经确定了一些针对 RNA 序列（目标 2）或 RNA 结构（目标 3）的命中并将在我们联盟的抗病毒药物研发管线中继续前进，对于 Nsp1 等其他药物来说，已经足够了。生物化学和细胞生物学可用信息，其中许多信息是由成员生成的我们的团队证明了针对 Nsp1 抑制剂的筛选的合理性。非常规病毒靶标将为开发针对其他病毒的新疗法打开大门具有未知酶功能的病毒产品，扩大了我们治疗病毒的药物空间感染。