权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Covalent inhibitors of host cell entry by SARS-CoV-2 for treatment of COVID-19

SARS-CoV-2 进入宿主细胞的共价抑制剂用于治疗 COVID-19

基本信息

批准号：
10611435
负责人：
Matthew Bogyo
金额：
$ 23.61万
依托单位：
STANFORD 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：
2022-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611435
关键词：
2019-nCoV ACE2 Animal Model Antibodies Antigens Azoles Bacteriophages Binding Biological Assay Biological Response Modifier Therapy COVID-19 COVID-19 therapeutics COVID-19 treatment Cell model Cells Chemistry China Complex Coronavirus Cyclic Peptides Development Disease Disease Outbreaks Enzyme-Linked Immunosorbent Assay Fluorides Fluorine Future Goals Health Human Infection Knowledge Libraries Ligand Binding Malignant Neoplasms Mass Spectrum Analysis Methods Modification Mutation Oral Patients Peptide Hydrolases Phage Display Pharmaceutical Preparations Point Mutation Production Proteins Proteomics Reaction Receptor Cell Resistance Resolution SARS-CoV-2 infection SARS-CoV-2 spike protein Serum Site Structure Sulfur Surface Technology Tertiary Protein Structure Test Result Testing Therapeutic Therapeutic Effect Therapeutic Uses Time Tyrosine Vaccines Variant Viral Viral Proteins Virus Virus Diseases cost economic impact high reward high risk in vivo inhibitor lead optimization mortality neutralizing antibody novel novel coronavirus pandemic disease pathogen prevent protein protein interaction receptor receptor binding screening small molecule success uptake validation studies viral outbreak

项目摘要

Project Summary Current strategies to overcome virus outbreaks are focused on development of effective vaccines as well as novel treatments that can either block infection or prevent mortality from the resulting disease. One of the strategies that has shown promise is the use of serum from patients who have recovered from infection. This strategy relies on the presence of high titers of neutralizing antibodies that bind to antigens on the virus and block uptake into host cells. For the SARS-CoV-2 virus this requires antibodies that bind to regions on the receptor binding domain (RBD) of the viral ‘spike’ (S) protein and block its interaction with the host receptor, angiotensin converting enzyme 2 (ACE2). Significant efforts over the past 15 years of studies on related coronaviruses has produced a detailed picture of the interactions between these two protein domains. These studies have facilitated strategies to select optimal neutralizing antibodies likely to have the greatest therapeutic value. While antibodies are effective biological therapies, they suffer from limitations that make their widespread use for a global pandemic limited. This includes the high cost of production, poor uptake by oral or localized administration and general incompatibility with long-term storage and stockpiling. Furthermore, interactions with the target viral proteins are reversible and can be rendered ineffective for antibody neutralization through single point mutations in virus variants. In this proposal, we outline plans to develop a phage display screening approach to identify synthetic cyclic peptides that carry a covalent ‘warhead’ to induce specific and permanent binding to the SARS-CoV-2 S protein at highly conserved and functionally important residues. This approach will lead to the identification of fully synthetic molecules that irreversibly block key interactions between the S protein RBD and the host cell receptor, ACE2. Such molecules will possess the selectivity of antibodies but can be synthesized and handled like small molecule drugs. Furthermore, their covalent binding mode will lead to prolonged therapeutic effects and reduced ability to induce resistance causing mutations in the S protein.

项目摘要目前克服病毒爆发的战略集中在开发有效的疫苗以及新的治疗方法，可以阻止感染或预防由此产生的疾病的死亡率。之一已经显示出希望的策略是使用从感染中恢复的患者的血清。这该策略依赖于存在高滴度的中和抗体，其结合病毒上的抗原，阻断宿主细胞的摄取。对于SARS-CoV-2病毒，这需要抗体结合到受体结合结构域（RBD），并阻断其与宿主受体的相互作用，血管紧张素转换酶2（ACE 2）。在过去15年中，冠状病毒已经详细描述了这两个蛋白质结构域之间的相互作用。这些研究促进了选择最佳中和抗体的策略，治疗价值虽然抗体是有效的生物疗法，但它们受到限制，它们对全球流行病的广泛使用受到限制。这包括生产成本高，口服或局部给药以及与长期储存和贮存的一般不相容。此外，委员会认为，与靶病毒蛋白的相互作用是可逆的，通过病毒变体中的单点突变进行中和。在这份提案中，我们概述了制定一项噬菌体展示筛选方法可识别携带共价“弹头”的合成环肽以诱导特异性和永久结合SARS-CoV-2S蛋白的高度保守和功能重要残基这种方法将导致识别完全合成的分子，不可逆地阻止关键的 S蛋白RBD和宿主细胞受体ACE 2之间的相互作用。这样的分子将拥有抗体的选择性，但可以像小分子药物一样合成和处理。而且他们的共价结合模式将导致延长的治疗效果和降低的诱导抗性的能力导致S蛋白发生突变