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Development of Novel Antivirals Targeting Viral RNA Methylation

针对病毒 RNA 甲基化的新型抗病毒药物的开发

基本信息

批准号：
10512630
负责人：
Danica Galonic Fujimori
金额：
$ 404.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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/10512630
关键词：
2019-nCoV Animal Model Antigen Presentation Antiviral Agents Binding Binding Sites Biochemistry Biological Assay C-terminal Cell model Cells Communicable Diseases Complex Coronavirus Coronavirus Infections Development Docking Drug Targeting Enzymes Exonuclease Exoribonucleases Family Genetic Transcription Guanidines Guanosine Triphosphate Head Human Immune Evasion Immune response In Vitro Industry Collaboration Innate Immune System Interferons Letters Libraries Ligand Binding Link MHC Class I Genes Messenger RNA Methylation Methyltransferase Middle East Respiratory Syndrome Coronavirus N-terminal Natural Immunity Nonstructural Protein Nucleotides Open Reading Frames Pharmaceutical Chemistry Pharmaceutical Preparations Proteins Proteomics RNA RNA Caps RNA methylation Role S-Adenosylmethionine SARS coronavirus SARS-CoV-2 genome SARS-CoV-2 infection Series Structure Testing Therapeutic Translations Viral Viral Proteins Virulence Virus Virus Diseases Virus Replication Work adaptive immunity antiviral drug development base cofactor high throughput screening in vivo industry partner inhibitor lead optimization loss of function mutation mRNA capping mutant novel pandemic disease poly A specific exoribonuclease programs response screening small molecule small molecule inhibitor small molecule libraries structural biology targeted agent viral RNA virology

项目摘要

PROJECT 4: DEVELOPMENT OF NOVEL ANTIVIRALS TARGETING VIRAL RNA METHYLATION SUMMARY Coronaviruses cap their RNA by coordinated action of two methyltransferases (MTase): Nsp14, which catalyzes N7-guanidine methylation of GTP at the 5′ terminus of viral RNAs, and Nsp16, which forms C2′-O-methyl- ribosyladenine at the subsequent nucleotide. By mimicking mRNA of the host cell, the resulting cap structure is critical for immune evasion, stabilization of viral RNA and efficient translation. While loss of function mutations in the MTase domain of Nsp14 are lethal to SARS-CoV-2, SARS-CoV strains that carry mutant Nsp16 have low virulence, suggesting that targeting of these enzymes, either alone or in combination with other viral proteins, has strong therapeutic potential. In this application, we propose to develop antiviral agents that target MTase activities of Nsp14 and Nsp16. Our approach will assess the potential of RNA capping MTases as a novel target family for development of antiviral agents. Importantly, since both enzymes are conserved across coronaviruses known to infect humans, this approach could provide a footprint for development of pan-coronaviral acting agents. Inhibitors for each of the MTases will be identified using a combination of small molecule discovery approaches: computational docking, fragment linking and merging, and high throughput screening (HTS) to identify novel chemotypes. Enabled by the recent developments in availability of make-on-demand libraries, we propose to use ultra-large library docking to identify candidate inhibitors. Availability of drug-like compounds in in-house small molecule libraries will facilitate inhibitor identification through HTS. Hit compounds will be tested in a series of activity assays and validated using direct binding strategies. Experimentally determined structures of MTases in complex with small molecule inhibitors will be used to guide optimization, aided by access to make-on-demand libraries. The identified inhibitors will be prioritized based on their selectivity against a comprehensive panel of human MTases and antiviral activity in cellular models of SARS-CoV-2 infection. The subsequent medicinal chemistry optimization and assessment of antiviral activity in animal models is expected to result in Optimized Lead compounds, which will be further elaborated by our industry partners (Roche).

项目四：开发针对病毒RNA甲基化的新型抗病毒药物