The severity and mortality of COVID-19 are associated with pre-existing medical comorbidities such as diabetes mellitus. However, the underlying causes for increased susceptibility to viral infection in patients with diabetes is not fully understood. Here we identify several small-molecule metabolites from human blood with effective antiviral activity against SARS-CoV-2, one of which, 1,5-anhydro-d-glucitol (1,5-AG), is associated with diabetes mellitus. The serum 1,5-AG level is significantly lower in patients with diabetes. In vitro, the level of SARS-CoV-2 replication is higher in the presence of serum from patients with diabetes than from healthy individuals and this is counteracted by supplementation of 1,5-AG to the serum from patients. Diabetic (db/db) mice undergo SARS-CoV-2 infection accompanied by much higher viral loads and more severe respiratory tissue damage when compared to wild-type mice. Sustained supplementation of 1,5-AG in diabetic mice reduces SARS-CoV-2 loads and disease severity to similar levels in nondiabetic mice. Mechanistically, 1,5-AG directly binds the S2 subunit of the SARS-CoV-2 spike protein, thereby interrupting spike-mediated virus–host membrane fusion. Our results reveal a mechanism that contributes to COVID-19 pathogenesis in the diabetic population and suggest that 1,5-AG supplementation may be beneficial to diabetic patients against severe COVID-19.

COVID-19 的严重程度和死亡率与先前存在的医学合并症有关，例如糖尿病。然而，糖尿病患者对病毒感染的易感性增加的根本原因尚不完全清楚。在这里，我们从人体血液中鉴定出几种对 SARS-CoV-2 具有有效抗病毒活性的小分子代谢物，其中之一是 1,5-anhydro- d-glucitol (1,5-AG)，与糖尿病有关。糖尿病患者的血清 1,5-AG 水平显着降低。在体外，糖尿病患者血清中的 SARS-CoV-2 复制水平高于健康个体，这可以通过在患者血清中补充 1,5-AG 来抵消。与野生型小鼠相比，糖尿病 (db/db) 小鼠经历 SARS-CoV-2 感染，伴随着更高的病毒载量和更严重的呼吸道组织损伤。在糖尿病小鼠中持续补充 1,5-AG 可将 SARS-CoV-2 载量和疾病严重程度降低到非糖尿病小鼠的相似水平。从机制上讲，1,5-AG 直接结合 SARS-CoV-2 刺突蛋白的 S2 亚基，从而中断刺突介导的病毒-宿主膜融合。