A thiol-saccharide therapy to treat COVID-19

治疗 COVID-19 的硫醇糖疗法

• 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
• 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

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.

covid - 19正在全球范围内引发前所未有的全球卫生突发事件，迫切需要新的治疗方法。在这项拨款申请中，我们建议确定MUC-031（一种二硫醇修饰的糖类）作为covid - 19治疗方法的治疗效用。我们目前正在开发muco -031作为一种新型的黏液解药，基于其在黏液凝胶中黏液蛋白聚合物之间的二硫交联的裂解能力。这些胱氨酸连接赋予病理黏液凝胶刚性和刚性。半胱氨酸还在维持SARS-CoV2刺突蛋白（SARS-2-S）受体结合域（RBD）的天然结合界面中发挥作用，SARS-CoV2刺突蛋白（SARS-2-S）作为进入受体与宿主细胞上的ACE2结合。我们假设SARS-2-S中胱氨酸的切割会改变RBD的天然构象，并使SARS-2-S与ACE2的结合失效。在平板结合实验的初步数据中，我们发现MUC-031在抑制SAR-2-S与ACE2的结合方面具有很强的活性，并且可以有效地阻止SARS- CoV2假病毒颗粒感染肺上皮细胞。我们提出了两个目标，以快速生成进一步的数据，以支持MUC-031作为covid - 19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。在本研究中，我们将使用平板结合试验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是否能改善covid - 19的体内治疗效果。在这里，我们将根据最近发表的该模型用于covid - 19研究的效用，使用叙利亚仓鼠模型。我们的共同目标将迅速确定MUC-031是否在covid - 19中具有治疗效用。我们的建议利用了现有tPPG的工作，并有望在相对较短的时间内产生一种新的治疗方法。这里提出的MUC-031的机制不同于所有其他正在测试的抗病毒疗法，它将增加阻止大流行的治疗方法。