Development of CoV inhibitors against non-enzymatic targets

针对非酶靶标的 CoV 抑制剂的开发

• 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
• 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

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.

摘要 使用病毒酶作为抗病毒开发的靶点，导致了许多用于治疗的抗病毒疗法 诊所。已经开发出几种针对艾滋病毒、丙型肝炎病毒和单纯疱疹病毒的病毒聚合酶和/或蛋白酶抑制剂，其中 其他。不太常见的是开发针对酶性质未知的病毒产品的抗病毒药物， 尽管有一些例外，包括用于治疗丙型肝炎病毒感染的NS5B抑制剂。同样多的病毒 产品缺乏明确的酶活性，可用于开发体外抑制物筛选试验，用途 将病毒酶作为治疗干预的靶标限制了可用的病毒靶标的数量。在项目4中- 针对这个抗病毒开发联盟的非酶靶点的冠状病毒抑制剂的开发，我们 探索酶活性未知且未被额外SARS-CoV-2覆盖的SARS-CoV-2靶点 这项建议的项目。我们选择了毒力所需的病毒蛋白Nsp1以及 病毒核糖核酸。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，我们将生化、遗传、结构和硅结合在一起 识别阻止Nsp1抑制宿主反应的治疗分子的方法 被感染的细胞。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 参与复制、转录和/或翻译的病毒RNA。在目标3中，我们计划识别分子 这结合并阻止了指导病毒RNA复制和转录的保守RNA结构的功能。 为此，我们组建了一支在使用RNA方面具有丰富专业知识的调查小组 治疗、病毒学、细胞生物学、RNA生物学和宿主-病毒相互作用。该团队与 该联盟的核心，以受益于结构、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。虽然该项目主要处于探索性阶段 阶段，已经确定了几个靶向RNA序列(目标2)或RNA结构(目标3)的命中 并将在我们财团的抗病毒管道中向前推进。对于其他人，如NSP1，有足够的 生化和细胞生物学可用的信息，其中许多信息是由 我们的团队，这证明了建议的Nsp1抑制剂筛查的合理性。这类抑制剂在抗肿瘤方面的研究进展 非常规病毒靶点将为开发针对其他病毒的新疗法和 未知酶功能的病毒产品，扩大了我们治疗病毒的可用药空间 感染。