Targeting galectin-3 to intervene COVID-19

以半乳糖凝集素 3 为靶点干预 COVID-19

基本信息

批准号：
10685248
负责人：
HAFIZ AHMED
金额：
$ 29.66万
依托单位：
GLYCOMANTRA, INC.
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：
2022-08-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685248
关键词：
2019-nCoV A549 ACE2 Affinity Agreement Alveolar Cell Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Anti-Inflammatory Agents Antiviral Therapy Binding Biological Assay Biological Availability Biological Markers Blood COVID-19 COVID-19 impact COVID-19 pandemic COVID-19 susceptibility COVID-19 treatment Cell Culture Techniques Cells Diabetes Mellitus Elderly Engineering Epithelial Cells Fatty acid glycerol esters Frequencies Future Galactose Binding Lectin Galectin 3 Glucose tolerance test Glycocalyx Glycoproteins Goals Healthcare Systems High Fat Diet Human Hypertension Immune Immune response In Vitro Incidence Infection Inflammation Inflammatory Insulin Receptor Insulin Resistance Interleukin-6 Legal patent Licensing Ligands Liver Lung Macrophage Measures Mediating Morbidity - disease rate Mucous body substance Mus Muscle Names Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Patients Penetration Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Phase 1/1b Clinical Trial Polysaccharides Population Prediabetes syndrome Production Proteins Publications Receptor Activation Receptor Signaling Receptor, Angiotensin, Type 1 Resolution Respiratory System Rodent Role SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 spike protein Source T-Lymphocyte TNF gene Technology Therapeutic Thick Toxic effect Transgenic Mice Viral Viral Load result Virus Virus Diseases alveolar epithelium antagonist cell bank cytokine cytokine release syndrome diabetic diabetic patient dietary experimental study fasting glucose glucose tolerance glycosylation humanized mouse hypertensive improved insulin sensitivity insulin signaling insulin tolerance knock-down mortality mouse model novel pandemic disease pharmacokinetics and pharmacodynamics primary endpoint receptor restoration secondary endpoint

项目摘要

Project Summary/Abstract The COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), is a global pandemic with catastrophic consequences for healthcare systems and populations. The increased morbidity and mortality in older persons and those with diabetes (12-22%) and hypertension (23.7-30%) is particularly concerning due to high incidence of diabetes throughout the world. The angiotensin-converting enzyme 2 (ACE2) receptor serves as a high affinity receptor for SARSCoV-2 to enter the lungs. Interestingly, patients with diabetes, who are treated with ACE inhibitor and angiotensin II type-I receptor blocker, highly express ACE2 making them more susceptible to COVID-19. For infection and pathogenesis, virus needs to attach and penetrate a thick glycan rich mucus and glycocalyx before binding its entry-receptor and galectin-3 (Gal3) is believed to play a role in the enhanced attachment of SARSCoV-2 through binding to the spike glycoprotein. Gal3 promotes viral infections and enhances of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α. We confirmed Gal3 binding to SARSCoV-2 spike glycoprotein. Interestingly, increased levels of Gal3 are associated with prediabetes, diabetes, and hypertension. Gal3 binds also directly to the insulin receptor (IR) and inhibits downstream IR signaling promoting obesity-mediated inflammation (macrophage-derived Gal3) and insulin resistance in type 2 diabetes (T2D). These fundamental observations elucidate a novel role of Gal3 that promotes viral infection and uncontrolled release of pro-inflammatory/anti- inflammatory cytokines and suggest that specific inhibition of Gal3 may represent a promising therapeutic strategy not only treat COVID-19, but also COVID-19 impacted diabetic patients. Our scientific premise is that we have developed a very potent Gal3 antagonist, named TFD100, from a natural dietary source (PNAS publication PMID: 23479624). In our preliminary studies, TFD100 inhibited replication of SARSCoV-2. TFD100 reversed Gal3 mediated inhibition of IR activation. TFD100 also decreased fasting glucose and improved glucose tolerance and insulin sensitivity. Here, we propose to investigate the therapeutic utilities of TFD100 for treating COVID-19 and COVID-19 impacted T2D in a relevant COVID-19 “humanized” mouse model (human ACE-2 transgenic mice). Following drug treatment of SARSCoV-2 infected mice, viral load (primary endpoint) and resolution of dysregulated inflammation (secondary endpoint) will be measured. To investigate TFD100’s ability to intervene COVID-19 impacted T2D in hACE-2 mice, obese- induced T2D will be made first in these mice with high fat diet followed by SARSCoV-2 infection. Following drug treatment, glucose and insulin tolerance as well as viral load (primary endpoints) will be measured. For other endpoints, resolution of host-response as dysregulated inflammation (cytokine storm) and restoration of insulin signaling will be measured by the frequency of pro-inflammatory/anti-inflammatory biomarkers (Gal3, ACE-2, and other proteins) in blood, lung, liver, fat, and muscle. This also includes determination of changes in pro/anti-inflammatory immune cell frequencies denoted by polarization of macrophages and helper-T (Th) cells. Gal3 inhibition is anticipated to be a significant advancement in the arsenal against SARSCoV-2 impacted T2D, and possibly SARSCoV-2 infection as an antiviral therapy.

项目摘要/摘要由严重的急性呼吸综合症冠状病毒2（SARSCOV-2）引起的Covid-19是全球大流行对医疗保健系统和人群造成灾难性后果。发病率增加尤其是老年人和糖尿病（12-22％）和高血压（23.7-30％）的死亡率关于全世界糖尿病的高气。血管紧张素转换酶2 （ACE2）受体是Sarscov-2进入肺部的高亲和力受体。有趣的是，患者与糖尿病（用ACE抑制剂和血管紧张素II型受体阻滞剂治疗的糖尿病 ACE2使它们更容易受到19号的影响。为了感染和发病机理，病毒需要附着和在结合其入口受体和galectin-3（gal3）之前，请穿透浓厚的聚糖粘液和糖蛋白浓汤据信通过结合与峰糖蛋白的结合在增强SARSCOV-2的附着中发挥作用。 GAL3促进病毒感染并增强促炎细胞因子，例如白介素（IL）-6，肿瘤坏死因子（TNF）-α。我们确认GAL3与SARSCOV-2尖峰糖蛋白结合。有趣的是，增加了 GAL3水平与糖尿病前，糖尿病和高血压有关。 gal3也直接与胰岛素受体（IR）并抑制促进肥胖介导的感染的下游IR信号传导（巨噬细胞衍生的GAL3）和2型糖尿病（T2D）中的胰岛素抵抗。这些基本观察阐明GAL3的新作用，促进了病毒感染并不受控制地释放促炎/抗炎炎症细胞因子，并提出对GAL3的特定抑制作用可能代表有前途的疗法策略不仅治疗了COVID-19，而且COVID-19还影响了糖尿病患者。我们的科学前提是，我们从一个自然饮食来源（PNAS出版物PMID：23479624）。在我们的初步研究中，TFD100抑制 SARSCOV-2的复制。 TFD100反向GAL3介导的IR激活抑制作用。 TFD100也减少了禁食葡萄糖和改善的葡萄糖耐受性和胰岛素敏感性。在这里，我们建议调查 TFD100治疗COVID-19和COVID-19的治疗实用程序在相关的Covid-19中影响T2D “人性化”小鼠模型（人ACE-2转基因小鼠）。在药物治疗SARSCOV-2感染后小鼠，病毒载荷（主要终点）和注射失调（次要终点）的分辨率将为测量。为了调查TFD100干预COVID-19的能力，影响了HACE-2小鼠的T2D，肥胖诱导的T2D将首先在这些小鼠中以高脂肪饮食进行，然后是SARSCOV-2感染。下列的将测量药物处理，葡萄糖和胰岛素耐受性以及病毒载量（主要终点）。为了其他终点，作为失调感染（细胞因子风暴）的宿主反应的分辨率和恢复胰岛素信号传导将通过促炎/抗炎生物标志物的频率（GAL3， ACE-2和其他蛋白质）在血液，肺，肝，脂肪和肌肉中。这还包括确定变化 pro/抗炎免疫细胞频率用巨噬细胞和辅助-T（Th）的极化表示细胞。预计GAL3抑制作用将是针对SARSCOV-2的武器库的重大进步受影响的T2D，可能是SARSCOV-2感染作为抗病毒疗法。