A glucose-like metabolite deficient in diabetes inhibits cellular entry of SARS-CoV-2

Abstract

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.The outcomes of a viral infection and disease progression are determined by complex host-virus interactions 1,2 . Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), presents highly heterogeneous clinical manifestations in humans 3,4 . The majority of individuals infected with SARS-CoV-2 have asymptomatic, mild or moderate disease; however, elderly individuals and patients with comorbidities such as type 2 diabetes mellitus are at a much higher risk of serious illness and even death 5 . Although complex immunological changes may underlie the vulnerability of these

Development of Equine Polyclonal Antibodies as a Broad-Spectrum Therapy Against SARS-CoV-2 Variants

“…Together with the H&E staining (Figure 3b) which showed well-organized structures and high similarities compared with nasal biopsy reported in the literatures (20)(21)(22), the nasal organoids were confirmed as successfully constructed. The 2-D airway organoids were then applied in the infection model as a testing platform for the neutralization effect of the antibodies.…”

Origin, virological features, immune evasion and intervention of SARS-CoV-2 Omicron sublineages

“…28 Nevertheless, their antiviral activity against other sublineages, such as BA.4 and BA.5, still needs further assessment. Besides, many preclinical antiviral agents, such as 1,5-anhydro-d-glucitol (1,5-AG), 70 and the pan-CoV fusion inhibitors, such as EK1 and EK1C4, 71 targeting the conserved site in S2 protein, also have good potential to broadly inhibit infection by SARS-CoV-2 variants and Omicron sublineages. For example, EK1 and EK1C4 can potently inhibit fusion mediated by S protein of WT SARS-CoV-2, Delta VOC, and Omicron BA.1.…”

SARS-CoV-2 omicron variant clearance delayed in breakthrough cases with elevated fasting blood glucose

“…Similar results were obtained in the present study during the Omicron variant wave. Glucose-like metabolite deficiency may facilitate viral entry and replication, as described previously [ 21 ]. Another mechanism is that the production of neutralizing antibodies is reduced in diabetes [ 18 , 26 ].…”

“…The in vitro experiment confirmed that increased glucose concentration decreases the viability of A549 cells and induces ACE2 overexpression [ 20 ]. In addition, viral loads are high, and respiratory tissue damage is severe in the diabetic mice model [ 21 ].…”