Targeting galectin-3 to intervene COVID-19

项目总结/摘要 由严重急性呼吸道综合征冠状病毒2（SARSCoV-2）引起的COVID-19是全球性的 大流行病对医疗保健系统和人口造成灾难性后果。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， 由于糖尿病在全世界的发病率很高，血管紧张素转换酶2 （ACE 2）受体作为SARSCoV-2进入肺的高亲和力受体。有趣的是，患者 在接受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中， ACE 2使他们更容易感染COVID-19。对于感染和发病，病毒需要附着， 在结合其进入受体和半乳糖凝集素-3（Gal 3）之前， 据信通过与刺突糖蛋白结合在增强SARSCoV-2的附着中起作用。 Gal 3促进病毒感染并增强促炎细胞因子如白细胞介素（IL）-6、肿瘤 肿瘤坏死因子-α。我们证实Gal 3与SARSCoV-2刺突糖蛋白结合。有趣的是， Gal 3的水平与前驱糖尿病、糖尿病和高血压有关。Gal 3也直接结合到 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 （巨噬细胞来源的Gal 3）和2型糖尿病（T2 D）中的胰岛素抵抗。这些基本的观察 阐明Gal 3促进病毒感染和促炎/抗炎细胞因子不受控制的释放的新作用。 并提示Gal 3的特异性抑制可能代表一种有前途的治疗方法 策略不仅治疗COVID-19，还治疗COVID-19影响的糖尿病患者。 我们的科学前提是，我们已经开发了一种非常有效的Gal 3拮抗剂，命名为TFD 100， 天然膳食来源（PNAS出版物PMID：23479624）。在我们的初步研究中，TFD 100抑制了 SARSCoV-2的复制。TFD 100逆转Gal 3介导的IR活化抑制。TFD 100也下降 空腹血糖和改善的葡萄糖耐量和胰岛素敏感性。在这里，我们建议调查 TFD 100用于治疗COVID-19和COVID-19影响相关COVID-19中的T2 D的治疗效用 “人源化”小鼠模型（人ACE-2转基因小鼠）。SARSCoV-2感染者的药物治疗后 小鼠、病毒载量（主要终点）和失调炎症的消退（次要终点）将被评估。 测定了为了研究TFD 100干预COVID-19影响的hACE-2小鼠T2 D的能力，肥胖- 诱导的T2 D将首先在具有高脂肪饮食的这些小鼠中产生，随后是SARSCoV-2感染。以下 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 其他终点，宿主应答作为失调性炎症（细胞因子风暴）的消退和 胰岛素信号传导将通过促炎/抗炎生物标志物（Gal 3， ACE-2和其他蛋白质）在血液、肺、肝、脂肪和肌肉中。这也包括确定 通过巨噬细胞和辅助T（Th）极化表示的促炎/抗炎免疫细胞频率 细胞Gal 3抑制预期是对抗SARSCoV-2的重要进展 受影响的T2 D和可能的SARSCoV-2感染作为抗病毒治疗。

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.