Apple-shaped obesity; a risky soil for cytokine-accelerated severity in COVID-19 (preprint)

Obesity is one of the most significant risk factors for the deterioration and mortality associated with COVID-19 [1]. A certain proportion of COVID-19 patients experience marked elevations of inflammatory mediators, termed “cytokine storm”, resulting in the deterioration of the respiratory condition [2,3]. In the present study, we elucidate that the high visceral adipose tissue (VAT) burden was more closely related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients than other obesity-associated markers, including body mass index (BMI). To explore a novel stratification of COVID-19 patients, we infected mouse-adapted SARS-CoV-2 in several obese mice, revealing that VAT-dominant ob/ob mice and diet-induced obesity obese mice died after infection with low-titer mouse-adapted SARS-CoV-2 virus due to the subsequent cytokine storm, whereas none of the subcutaneous adipose tissue (SAT) dominant db/db mice or control lean wild-type mice died. SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased production of inflammatory cytokine represented by IL-6. As well as the anti-IL-6 treatment, the prevention of obesity by leptin administration improved the survival of SARS-CoV-2 infected ob/ob mice by reducing the viral protein burden and excessive immune responses.

Identification of anti-severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) oxysterol derivatives in vitro (preprint)

Development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are urgently needed to combat the coronavirus disease 2019 (COVID-19). Oxysterols, defined as oxidized derivatives of cholesterol, include endogenous (naturally occurring) cholesterol metabolites as well as semi-synthetic oxysterol derivatives. We have previously studied the use of semi-synthetic oxysterol derivatives as drug candidates for inhibition of cancer, fibrosis, and bone regeneration. In this study, we have screened a panel of naturally occurring and semi-synthetic oxysterol derivatives for anti-SARS-CoV-2 activity, using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22( R )-hydroxycholesterol, 24( S )-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy186 displayed antiviral activity comparable to natural oxysterols. In addition, related oxysterol analogues Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fall into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell culture infection assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 with disrupting the formation of double membrane vesicles (DMVs), intracellular membrane compartments associated with viral replication. Oxy210 also inhibited the replication of hepatitis C virus, another RNA virus whose replication is associated with DMVs, but not the replication of the DMV-independent hepatitis D virus. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk developing COVID-19.