Targeting galectin-3 to intervene COVID-19

项目摘要/摘要 新冠肺炎由严重急性呼吸综合征冠状病毒2型引起，是一种全球性的 大流行对医疗保健系统和人口造成灾难性后果。发病率的增加 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 由于糖尿病在世界各地的高发病率，人们对此感到担忧。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，病人 接受血管紧张素II受体阻滞剂和血管紧张素转换酶抑制剂治疗的糖尿病患者，高度表达 血管紧张素转换酶2使他们更容易感染新冠肺炎。对于感染和发病机制，病毒需要依附和 在与其进入受体和Galectin-3(Galectin-3)结合之前，穿透厚厚的富含多糖的粘液和糖萼 据信通过与尖峰糖蛋白结合，在增强SARSCoV-2的附着方面发挥了作用。 Gal3促进病毒感染并增强促炎症细胞因子，如白介素6、肿瘤 肿瘤坏死因子α。我们证实了Gal3与SARSCoV-2刺突糖蛋白的结合。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还直接绑定到 胰岛素受体(IR)及其抑制促进肥胖介导的炎症反应的IR下游信号 (巨噬细胞衍生的Gal3)与2型糖尿病的胰岛素抵抗(T2D)。这些基本的观察结果 阐明Gal3促进病毒感染和不受控制的促炎/抗炎因子释放的新作用 炎性细胞因子，提示Gal3的特异性抑制可能是一种有前途的治疗方法 策略不仅治疗新冠肺炎，还影响新冠肺炎糖尿病患者。 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，它是从一种 天然饮食来源(美国国家科学院出版物PMID：23479624)。在我们的初步研究中，TFD100抑制了 复制SARSCoV-2病毒。TFD100逆转Gal3对IR激活的抑制作用。TFD100也有所下降 空腹血糖和改善的糖耐量和胰岛素敏感性。在这里，我们建议调查 TFD100对新冠肺炎的治疗作用及新冠肺炎对相关新冠肺炎T2D的影响 “人源化”小鼠模型(人ACE-2转基因小鼠)。SARSCoV-2感染后的药物治疗 小鼠，病毒载量(主要终点)和失调炎症的解决(次要终点)将是 量过了。[目的]探讨TFD100‘S干预新冠肺炎对HACE-2小鼠T2D影响的能力。 在这些高脂饮食的小鼠中，首先进行T2D诱导，然后再进行SARSCoV-2感染。跟随 将测量药物治疗、血糖和胰岛素耐量以及病毒载量(主要终点)。为 其他终点，作为失调炎症(细胞因子风暴)的宿主反应的解决和恢复 胰岛素信号将通过促炎/抗炎生物标志物(Gal3， 血管紧张素转换酶-2和其他蛋白质)。这还包括确定 以巨噬细胞和辅助性T细胞(Th)极化表示的促炎/抗炎免疫细胞频率 细胞。Gal3的抑制预计将是对抗SARSCoV-2的武器库的重大进步 影响T2D，并可能作为抗病毒治疗的SARSCoV-2感染。

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.