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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.

总结