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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.

项目概要/摘要 COVID-19 是由严重急性呼吸综合征冠状病毒 2 (SARSCoV-2) 引起的全球性流行病大流行给医疗保健系统和人口带来灾难性后果。发病率增加老年人、糖尿病患者 (12-22%) 和高血压患者 (23.7-30%) 的死亡率尤其高由于世界范围内糖尿病的高发病率而令人担忧。血管紧张素转换酶2 (ACE2) 受体作为 SARSCoV-2 进入肺部的高亲和力受体。有趣的是，患者接受 ACE 抑制剂和血管紧张素 II-I 型受体阻滞剂治疗的糖尿病患者，高表达 ACE2 使他们更容易感染 COVID-19。为了感染和发病，病毒需要附着和在结合其进入受体和半乳糖凝集素 3 (Gal3) 之前，先穿透厚厚的富含聚糖的粘液和糖萼据信通过与刺突糖蛋白结合，在增强 SARSCoV-2 的附着方面发挥作用。 Gal3 促进病毒感染并增强促炎细胞因子，例如白细胞介素 (IL)-6、肿瘤坏死因子（TNF）-α。我们确认 Gal3 与 SARSCoV-2 刺突糖蛋白结合。有趣的是，增加了 Gal3 水平与糖尿病前期、糖尿病和高血压有关。 Gal3 也直接结合胰岛素受体 (IR) 并抑制下游 IR 信号传导，促进肥胖介导的炎症（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 促进病毒感染和促炎/抗炎物质不受控制释放的新作用炎症细胞因子，表明对 Gal3 的特异性抑制可能是一种有前途的治疗方法该策略不仅可以治疗 COVID-19，还可以治疗受 COVID-19 影响的糖尿病患者。我们的科学前提是我们已经开发出一种非常有效的 Gal3 拮抗剂，名为 TFD100，来自天然膳食来源（PNAS 出版物 PMID：23479624）。在我们的初步研究中，TFD100 抑制 SARSCoV-2 的复制。 TFD100 逆转 Gal3 介导的 IR 激活抑制。 TFD100也下降了空腹血糖并改善葡萄糖耐量和胰岛素敏感性。在此，我们建议调查 TFD100 用于治疗相关 COVID-19 和受 COVID-19 影响的 T2D 的治疗效用 “人源化”小鼠模型（人类 ACE-2 转基因小鼠）。对 SARSCoV-2 感染者进行药物治疗后小鼠，病毒载量（主要终点）和失调炎症的解决（次要终点）将测量。为了研究 TFD100 干预 hACE-2 小鼠、肥胖小鼠中受 COVID-19 影响的 T2D 的能力，这些高脂肪饮食的小鼠首先会诱发 T2D，然后感染 SARSCoV-2。下列的将测量药物治疗、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，宿主反应作为失调炎症（细胞因子风暴）的解决和恢复胰岛素信号传导将通过促炎/抗炎生物标志物（Gal3、 ACE-2 和其他蛋白质）存在于血液、肺、肝脏、脂肪和肌肉中。这还包括确定变化促/抗炎免疫细胞频率由巨噬细胞和辅助 T (Th) 的极化表示细胞。 Gal3 抑制预计将成为对抗 SARSCoV-2 的重大进步作为一种抗病毒疗法，它影响了 T2D，也可能影响了 SARSCoV-2 感染。