A pathway to down regulate ACE2 — the receptor that facilitates SARS-CoV-2 entry into cells — is identified in a paper publishing in Nature. A clinically approved drug that targets this pathway is shown to reduce SARS-CoV-2 infection in a range of models, including in organoids and corresponding tissues in animals and humans. Preventing infection by modulating the viral host receptors could complement vaccination and may be useful for certain vulnerable groups.
Some high-risk individuals, such as immunocompromised patients, may not develop appropriate responses to COVID-19 vaccines. Targeting viral host receptors, which are essential for infection, may be an attractive alternative approach. ACE2 is the main receptor for SARS-CoV-2, but the mechanisms controlling the expression of this receptor remain poorly understood, making it difficult to find treatments that will modify its expression and prevent infection.
Fotios Sampaziotis and colleagues identify a receptor called FXR that directly modifies the expression of ACE2 in tissues affected by SARS-CoV-2, including the lungs and the digestive tract. They go on to test drugs that can inhibit FXR and show that ursodeoxycholic acid (UDCA, used to treat some liver diseases) downregulates ACE2 in lung, bile duct and intestinal organoids, as well as in corresponding tissues in mice and hamsters. UDCA is shown to reduce ACE2 in nasal cells of healthy volunteers and prevent infection in human lungs and livers maintained in the laboratory. Moreover, the authors use retrospective clinical data to reveal that UDCA treatment is correlated with improved outcomes following SARS-CoV-2 infection, a finding that they validate in an independent group of liver transplant recipients.
These findings demonstrate that FXR is a new therapeutic target for the treatment of COVID-19 and suggest a potential correlation between UDCA treatment and positive clinical outcome for patients with COVID-19.
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