Abstract
Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Here, the first structure of serum albumin in complex with dexamethasone is reported. Dexamethasone binds to drug site7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with an analysis of publicly available clinical data from Wuhan and suggests that an adjustment of the dexamethasone regimen should be further investigated as a strategy for patients affected by two major COVID-19 risk factors: low albumin levels and diabetes.
Highlights
On 16 June 2020, collaborators in the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial reported that a daily dose of 6 mg dexamethasone reduced deaths among COVID-19 patients receiving respiratory interventions (Ledford, 2020; RECOVERY/University of Oxford, 2020)
The crystal structure of equine serum albumin (ESA) in complex with dexamethasone was determined at 2.4 Aresolution
We propose that further research should be performed to evaluate adjusting the dexamethasone dosing regimen as a strategy for patients with severe COVID-19 and with hypoalbuminemia, diabetes or co-administration of large doses of drugs that bind to drug site 7 (DS7)
Summary
On 16 June 2020, collaborators in the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial reported that a daily dose of 6 mg dexamethasone reduced deaths among COVID-19 patients receiving respiratory interventions (Ledford, 2020; RECOVERY/University of Oxford, 2020). This widely available steroid has been shown to cut deaths by approximately 30% for patients who were on ventilators and by 20% for those who were receiving oxygen therapy but were not on ventilators. Dexamethasone suppresses the immune system by binding to the glucocorticoid receptor, which up-regulates the expression of antiinflammatory proteins and down-regulates the expression of pro-inflammatory proteins (Rhen & Cidlowski, 2005). The reduced inflammation provides some relief for patients whose lungs have been devastated by the overactive immune
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