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Core E – Structural Biology

核心 E — 结构生物学

基本信息

批准号：
10513940
负责人：
Jason Scott McLellan
金额：
$ 169.98万
依托单位：
EMORY UNIVERSITY
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/10513940
关键词：
2019-nCoV Address Affinity Amino Acids Antiviral Agents Area Binding Biological Assay Biophysics COVID-19 pandemic Calorimetry Collection Complex Consult Coronavirus Cryoelectron Microscopy Crystallization Data Data Set Development Drops Drug Design Electron Microscope Electrons Entropy Formulation Image Insecta Intervention Kinetics Knowledge Laboratories Lead Mammalian Cell Mission Molecular Conformation Molecular Mechanisms of Action Oral Pharmaceutical Preparations Plasmids Polymerase Process Production Property Protein Engineering Proteins RNA Viruses Research Personnel Research Project Grants Resistance Resolution Respiratory syncytial virus Roentgen Rays SARS coronavirus Services Structure Surface Surface Plasmon Resonance Techniques Texas Thermodynamics Titrations Universities Validation Variant Viral Proteins Work X-Ray Crystallography austin base biophysical properties biophysical techniques design detector drug development experience flexibility improved in silico inhibitor insight instrument lead optimization novel pandemic disease particle pathogenic virus protein expression protein purification protein structure rational design screening small molecule structural biology synchrotron radiation virology

项目摘要

Project Summary – Core E There is an urgent need for the development of orally bioavailable antivirals that are safe and highly efficacious against coronaviruses such as SARS-CoV-2 as well as other RNA viruses with pandemic potential. The development of effective small-molecule antivirals can be greatly accelerated by a thorough understanding of their biophysical binding constants, mechanisms of action, and structural basis of binding, which will be provided by Core E: Protein Expression and Structural Biology. This core will be led by Dr. Jason McLellan at the University of Texas at Austin, who is an expert in structural virology and the development of structure-based interventions for viral pathogens. His laboratory has expertise in the determination of viral protein structures, including the first structure of the respiratory syncytial virus (RSV) polymerase complex, as well as extensive experience in structure-based design and biophysical characterization of protein interactions. The primary mission of Core E of the Antiviral Countermeasures Development Center (AC/DC) is to determine X-ray or cryo-EM structures of lead compounds identified by the Research Projects in complex with their viral protein targets. The resulting atomic-level information will be used to rationally design or optimize lead compounds in silico, as well as determine molecular mechanisms of action. Core E will also provide protein expression and purification support to Research Projects that need highly active and pure proteins for compound validation or novel screening approaches. Additionally, Core E will perform biophysical binding studies to determine thermodynamic and kinetic binding constants for lead compounds via isothermal titration calorimetry and surface plasmon resonance. These techniques can be used to identify candidates that bind directly to the target protein as well as enable compound optimization aimed at improving specific binding parameters. Collectively, the services provided by Core E will accelerate the development of orally bioavailable antivirals against SARS-CoV-2 and other RNA viruses with pandemic potential as well as provide novel insights into the structure, function, and inhibition of important viral proteins.

项目总结-核心E