While healthcare workers and public health officials have been fighting on the front lines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections that cause the devastating symptoms of COVID-19, researchers have been working to understand how the virus causes the symptoms of the disease and to identify the best treatments. Recent research based on x-ray data collected at the U.S. Department of Energy’s Advanced Photon Source (APS) has provided important insights into how dexamethasone, a drug used to treat COVID-19 patients, is transported within the body and the factors that may determine whether it helps or harms these vulnerable patients. Their results were the cover article in the IUCr Journal.
Dexamethasone is a commonly used corticosteroid drug that gained global attention in June, 2020, when it was reported to reduce death rates by 20%-30% in COVID-19 patients who have respiratory symptoms that require them to be on ventilation or oxygen. However, although the therapeutic actions of dexamethasone are quite well understood, what is less well studied is the way the drug gets to its targets via the bloodstream. This is important because, like most drugs, dexamethasone works within a “window” of therapeutic efficacy and can have off-target side effects if too high a dose is administered. In the blood, dexamethasone is transported by a very abundant protein called albumin. The drug exists in an equilibrium between the albumin-bound form and a pharmacologically active “free” form. Factors that affect this equilibrium can change how much active dexamethasone is in the bloodstream and make the difference between helpful efficacy and harmful side effects.
In an international collaboration led by a team from the University of Virginia, scientists from the United States and Poland conducted experiments at the APS, a DOE Office of Science user facility at Argonne National Laboratory. Their study focused on learning more about the interactions between serum albumin and dexamethasone by solving the crystal structure for this drug-protein complex to 2.4-Å resolution at the Life Sciences Collaborative Access Team (LS-CAT) 21-ID-F beamline at the APS. The structure (Fig. 1) showed that dexamethasone binds between two subdomains of albumin, which is known to have 10 drug binding sites. The dexamethasone binding site (drug site 7) is already known to bind non-steroidal anti-inflammatory drugs (like ibuprofen), the hormone testosterone, and anesthetics. This highlights the fact that other albumin cargoes could affect dexamethasone levels in the blood. Many of the drugs that are commonly used for COVID-19 patients are known to bind to serum albumin, but their binding sites are not necessarily known. If they compete for dexamethasone binding at site 7, this could impact the therapeutic effects of dexamethasone. Also, the impact of testosterone binding to the same site is interesting as low testosterone levels are a predictor of poor outcomes in COVID-19 and this is suspected to be a contributing factor in why more men die of COVID-19 than women. Dexamethasone in too high a dose could compete with testosterone for albumin binding and affect its transport, further exacerbating the impact of low testosterone.
The team extended their structural findings by analyzing data from patients admitted to the hospital for COVID-19 in Wuhan, China, early in 2020 to understand the role of albumin transport in determining outcomes in COVID-19 patients. Their first observation was that patients who died of COVID-19 had lower than normal albumin levels and also lower albumin levels compared to those who survived. Although low albumin is a well-recognized risk factor during critical disease, it is important to be aware of this possibility when treating COVID-19 patients with dexamethasone. The Wuhan patients who died also had higher blood glucose levels than those who survived. This finding supports public health advice that patients with diabetes are at higher risk for serious COVID-19 disease. The high blood sugar could also result in modifications of albumin at site 7 and affect its ability to bind dexamethasone and other cargoes.
Dexamethasone is certainly an important treatment for COVID-19, but this study suggests that its administration should potentially be adjusted according to patient risk factors such as albumin levels and diabetes to be sure they achieve the benefits of treatment and not the harms of excess dosing. ― Sandy Field
See: Ivan G. Shabalin1, Mateusz P. Czub1, Karolina A. Majorek1‡, Dariusz Brzezinski1,2, 3, Marek Grabowski1, David R. Cooper1, Mateusz Panasiuk4, Maksymilian Chruszcz5, and Wladek Minor1*, “Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy,” IUCrJ 7(6) 1048 (November 2020). DOI: 10.1107/S2052252520012944
Author affiliations: 1University of Virginia, 2Polish Academy of Sciences, 3Poznan University of Technology, 4Medical University of Bialystok, 5University of South Carolina ‡Present address: The Beatson Institute for Cancer Research
Correspondence: *wladek@iwonka.med.virginia.edu
We thank Keith Brister, Zdzislaw Wawrzak, Spencer Anderson, and Joseph Brunzelle at LS-CAT Sector 21 for their assistance in data collection. This work was supported by the National Institute of General Medical Sciences grants R01-GM132595 and U54-GM094662. D.B. acknowledges the support of the Polish National Agency for Academic Exchange (grant No. PPN/BEK/2018/1/00058/U/00001) and Polish National Science Center (grant No. 2020/ 01/0/NZ1/00134). M.P.C. acknowledges the support of the Robert R. Wagner Fellowship at the University of Virginia. M.C. was partially supported by a COVID-19 Research Initiative grant from the Office of the Vice President for Research at the University of South Carolina. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory. Extraordinary facility operations were supported in part by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act.
The U.S. Department of Energy's APS is one of the world’s most productive x-ray light source facilities. Each year, the APS provides high-brightness x-ray beams to a diverse community of more than 5,000 researchers in materials science, chemistry, condensed matter physics, the life and environmental sciences, and applied research. Researchers using the APS produce over 2,000 publications each year detailing impactful discoveries, and solve more vital biological protein structures than users of any other x-ray light source research facility. APS x-rays are ideally suited for explorations of materials and biological structures; elemental distribution; chemical, magnetic, electronic states; and a wide range of technologically important engineering systems from batteries to fuel injector sprays, all of which are the foundations of our nation’s economic, technological, and physical well-being.
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