A thiol-saccharide therapy to treat COVID-19

治疗 COVID-19 的硫醇糖疗法

基本信息

批准号：
10226074
负责人：
John V Fahy
金额：
$ 76.85万
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：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226074
关键词：
2019-nCoV Aerosols Animal Model Animals Anti-Inflammatory Agents Antioxidants Antiviral Agents Antiviral Therapy Applications Grants Binding Biological Assay Biomedical Research COVID-19 Carbohydrates Cell Culture System Cell Culture Techniques Cells Characteristics Cleaved cell Clinic Collaborations Coronavirus Cystine Cytokine Activation Data Development Diffuse Disease Disulfide Linkage Disulfides Dose Epithelial Cells Equilibrium Funding Gel Glycoproteins HIV Hamsters Histopathology Human In Vitro Infection Infection prevention Inflammation Inhalation Interferon-alpha Interferons Lead Lung Lung diseases Lung infections Mediator of activation protein Mesocricetus auratus Modeling Molecular Conformation Morbidity - disease rate Mucins Mucolytics Mucous body substance Nasal Epithelium National Heart, Lung, and Blood Institute Outcome Pathologic Pathology Peptidyl-Dipeptidase A Pharmaceutical Preparations Pneumonia Polymers Program Development Property Proteins Publications Reaction Receptor Cell Research Research Institute Rodent Role Severe Acute Respiratory Syndrome Solubility Source Sulfhydryl Compounds Surface Testing Therapeutic Therapeutic Agents Time Tissues Toxicology Trehalose Up-Regulation Viral Viral Load result Viral Physiology Virus Virus Diseases Weight Work aerosolized airway epithelium base chemical reduction crosslink dithiol drug development effective therapy env Gene Products global health emergency improved in vivo indexing lung injury mortality novel pandemic disease pre-clinical prevent programs receptor receptor binding respiratory

项目摘要

ABSTRACT COVID19 is causing an unprecedented global health emergency worldwide and new treatments are urgently needed. In this grant application we propose to determine the therapeutic utility of MUC-031 - a dithiol modified saccharide - as a treatment for COVID19. We are currently developing MUC-031 as a novel mucolytic based on its ability to cleave disulfide crosslinks between mucin polymers in mucus gels. These cystine linkages confer stiffness and rigidity to pathologic mucus gels. Cystines also have roles in maintaining the native binding interface in the receptor binding domain (RBD) of the SARS-CoV2 spike (S) protein (SARS-2-S), which binds ACE2 on host cells as an entry receptor. We hypothesize that cleavage of cystines in SARS-2-S will alter the native conformation of the RBD and disable SARS-2-S binding to ACE2. In preliminary data in a plate-binding assay, we find that MUC-031 is highly potent in inhibiting SAR-2-S binding to ACE2 and effective in preventing SARS- CoV2 pseudovirions from infecting lung epithelial cells. We propose two aims to quickly generate further data to support MUC-031 as a novel treatment for COVID19. AIM 1 will determine if MUC-031 disables SARS-2-S in vitro to inhibit SARS-CoV2 infection. In this Aim we will use a plate binding assay and cell culture systems to determine the dose and time determinants of MUC-031 inhibition of SARS-2-S binding to ACE2 and SARS-CoV2 infection of cells. AIM 2 will determine if MUC-031 improves COVID19 outcomes in vivo. Here we will use a Syrian hamster model of COVID19 based on recent publication of the utility of this model for COVID19 research. Together our aims will quickly determine if MUC-031 has therapeutic utility in COVID19. Our proposal leverages work in an existing tPPG and holds promise to yield a novel treatment in a relatively short timeframe. The mechanism of MUC-031 proposed here is distinct from that of all other anti-viral therapies being tested, and will add to the arsenal of treatments to stop the pandemic.

摘要：新冠肺炎 (COVID19) 正在全球范围内引发前所未有的全球卫生紧急情况，迫切需要新的治疗方法。在本次拨款申请中，我们建议确定 MUC-031（一种二硫醇修饰糖）作为治疗 COVID19 的治疗效用。我们目前正在开发 MUC-031 作为一种新型粘液溶解剂，因为它能够裂解粘液凝胶中粘蛋白聚合物之间的二硫键交联。这些胱氨酸连接赋予病理性粘液凝胶刚度和刚度。胱氨酸还在维持 SARS-CoV2 刺突 (S) 蛋白 (SARS-2-S) 的受体结合域 (RBD) 中的天然结合界面方面发挥作用，该蛋白作为进入受体结合宿主细胞上的 ACE2。我们假设 SARS-2-S 中胱氨酸的裂解将改变 RBD 的天然构象，并使 SARS-2-S 无法与 ACE2 结合。在板结合试验的初步数据中，我们发现MUC-031能够高效抑制SAR-2-S与ACE2的结合，并有效防止SARS-CoV2假病毒颗粒感染肺上皮细胞。我们提出了两个目标，即快速生成更多数据以支持 MUC-031 作为 COVID19 的新型治疗方法。 AIM 1将确定MUC-031是否在体外禁用SARS-2-S以抑制SARS-CoV2感染。在此目标中，我们将使用平板结合测定和细胞培养系统来确定 MUC-031 抑制 SARS-2-S 与 ACE2 结合和 SARS-CoV2 感染细胞的剂量和时间决定因素。 AIM 2 将确定 MUC-031 是否可以改善 COVID19 的体内结果。在这里，我们将使用新冠肺炎叙利亚仓鼠模型，基于最近发布的该模型在新冠肺炎研究中的实用性。我们的共同目标将是快速确定 MUC-031 是否对 COVID19 具有治疗作用。我们的提案利用了现有 tPPG 的工作，并有望在相对较短的时间内产生一种新颖的治疗方法。这里提出的 MUC-031 的机制与正在测试的所有其他抗病毒疗法不同，并将增加阻止大流行的治疗方法。