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Coronavirus antiviral nucleoside analogs: inhibition and reduced susceptibility

冠状病毒抗病毒核苷类似物：抑制和降低敏感性

基本信息

批准号：
9396306
负责人：
Maria Agostini
金额：
$ 2.87万
依托单位：
VANDERBILT UNIVERSITY
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：
2017-09-30 至 2020-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9396306
关键词：
5&apos -exoribonuclease Adenosine Affect Antiviral Agents Antiviral Therapy Blood Circulation Collaborations Common Cold Complex Coronaviridae Coronavirus Coronavirus Infections Defective Viruses Development Disease Excision Exons Exoribonucleases Family Fingers Future Genome Goals HIV Health Hepatitis B Hepatitis C Herpesviridae Human Individual Infection Institutes Interruption Life Cycle Stages Lung diseases Mediating Mediator of activation protein Middle East Respiratory Syndrome Coronavirus Modeling Murine hepatitis virus Mutagenesis Mutation Nonstructural Protein Northern Blotting Nucleic Acids Nucleosides Nucleotides Polymerase Population Predisposition RNA Viruses RNA chemical synthesis RNA replication RNA-Directed RNA Polymerase Regulation Reporting Research Ribavirin Role Science Severe Acute Respiratory Syndrome Syndrome Testing Therapeutic Time Vaccine Therapy Vaccines Viral Virus Virus Replication Zoonoses antiviral nucleoside analog clinical development clinically relevant combat cytotoxicity deep sequencing drug development drug discovery experimental study fitness improved inhibitor/antagonist insight mortality nucleoside analog pandemic disease resistance mutation respiratory tool viral RNA viral fitness

项目摘要

PROJECT SUMMARY Coronaviruses (CoVs) are a family of positive-sense RNA viruses that cause respiratory illnesses in humans ranging from the common cold to severe and lethal disease. The emergence of SARS-coronavirus (CoV) in 2002 and the continued circulation of MERS-CoV emphasize the capacity of CoVs to cause new zoonotic infections with pandemic potential. Despite the high mortality rates of these infections, no therapeutics or vaccines against any CoVs are currently available. Broadly active antiviral nucleoside analogs such as Ribavirin (RBV) are ineffective against CoVs. This limitation is attributed to a unique proofreading exoribonuclease (ExoN) in nonstructural protein 14 (nsp14-ExoN) that aids the RNA-dependent RNA polymerase (RdRp) encoded in nonstructural protein 12 (nsp12-RdRp) in high fidelity replication of these large positive-strand RNA viruses. We have identified two antiviral nucleoside analogs, GS-5734 and EIDD-1931, in collaboration with Gilead Sciences and the Emory Institute for Drug Development, respectively, which are broadly active against multiple CoVs with minimal cytotoxicity. In addition, we have identified two mutations within the predicted fingers domain of the nsp12-RdRp that reduce susceptibility to GS-5734, a C-adenosine nucleoside analog. The goals of this proposal are to define mechanisms through which these antiviral compounds inhibit CoV replication and determine the impact of resistance mutations on viral fitness, replication fidelity, and nucleotide selectivity. In Specific Aim 1, the basis of GS-5734 and EIDD-1931-mediated inhibition of CoV replication will be defined using deep sequencing, RT-qPCR, and Northern blot analysis to distinguish between the two most common mechanisms of antiviral action displayed by nucleoside analogs: chain termination and lethal mutagenesis. Experiments proposed in Specific Aim 2 will determine the impact of mutations that reduce susceptibility to GS-5734 and EIDD-1931 on coronavirus replication fidelity, viral fitness, and susceptibility to other nucleoside analogs. Together, these studies will probe mechanisms of GS-5734 and EIDD-1931 inhibition of CoV replication and explore the potential for these antiviral nucleoside analogs to individually and cooperatively serve as potent therapies against existing and emerging CoVs. This research also will inform the development of broadly active and complementary antiviral approaches to combat CoV infections. Finally, these studies will utilize GS-5734 and EIDD-1931 as tools to better understand mechanisms and viral mediators of CoV replication efficiency and fidelity.

项目总结