Repurposing UDCA, an FXR Inhibitor, to Prevent SARS-Cov-2 Infection

Abstract

Brevini T, Maes M, Webb GJ, et al. FXR Inhibition May Protect From SARS-CoV-2 Infection by Reducing ACE2. Nature 2022 Dec 5. https://doi.org/10.1038/s41586-022-05594-0. Viruses need to access the host’s machinery to replicate and propagate, and do so by binding to their respective receptors on host cells. Angiotensin-converting enzyme 2 (ACE2) was identified early in the pandemic as the entryway for the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Since then, scientists have been exploring ways to prevent SARS-Cov-2 infection by targeting ACE2. In a study published in Nature, Brevini et al identified farnesoid X receptor (FXR) as a regulator of ACE2 expression. FXR is a ubiquitous bile acid sensing protein. Upon its activation by chenodeoxycholic acid, ACE2 increased in biliary, airway, and intestinal organoids. FXR directly bound the ACE2 promoter and activated its transcription. Furthermore, suppressing FXR signaling with ursodeoxycholic acid (UDCA) or Z-guggulsterone–reduced ACE2 expression. To test its relevance to coronavirus disease 2019 (COVID-19) in vitro, organoids were stimulated with chenodeoxycholic acid and infected with SARS-Cov-2 in the presence or absence of UDCA or Z-guggulsterone. Reduced viral infection was measured when drugs were present. In vivo, UDCA treatment decreased ACE2 expression in tissues of mice and hamsters. Furthermore, the Syrian Hamster model showed replication and transmission of SARS-Cov-2 in all untreated animals, whereas only 3 of 9 UDCA-treated animals were infected, and they presented a milder disease course. Interestingly, the authors took several approaches to validate their findings in the human context. They first used donated organs that were unfit for transplantation. They performed ex situ normothermic perfusion on a pair of lungs, whereby 1 lung received UDCA in the perfusate and the other served as a matched control. UDCA treatment decreased ACE2 expression in lung cells and ACE2 activity in the perfusate. Importantly, UDCA treatment decreased infection when lungs were exposed to SARS-Cov-2. Similar observations were seen with liver grafts. Additionally, they determined that UDCA reduced ACE2 expression in the nasal epithelium of healthy volunteers who received UDCA. They also retrospectively found an inverse correlation between UDCA and serum ACE2 levels in a serum proteomics dataset of a patient cohort. Finally, the authors interrogated 2 COVID-19 databases, one composed of patients with chronic liver disease and the other of vaccinated liver transplant recipients. In both scenarios, patients receiving UDCA had better COVID-19 outcomes compared with matched controls. Brevini et al were clever in their approaches. They repurposed donated organs found unfit for transplantation, giving them a new benefit for preclinical drug testing with potentially better predictive power. More important, they repurposed an approved and off-patent drug, UDCA, to prevent SARS-Cov-2 infection, a novel approach against viral infection that is directed toward the host rather than the virus. Because ACE2 is a receptor for many viruses, UDCA may have broader use and is less susceptible to immune escape by viruses. Although the experimental data shown were strong, it remains to be seen how UDCA performs in clinical trials involving larger and controlled cohorts of patients. Nonetheless, the repurposing of a cost-effective and readily available drug to prevent viral infection alongside vaccination is exciting and promising.