Baricitinib is a Janus-associated kinase inhibitor (JAK inhibitor) acting against JAK1 and JAK2. It is currently approved by regulatory agencies (including US FDA, EMA and HSA) to treat rheumatoid arthritis.
Artificial intelligence has identified a group of drugs (including baricitinib) that could inhibit receptormediated endocytosis, which is the mechanism that most viruses use to enter cells. A known regulator of endocytosis is the adaptor-associated protein kinase-1 (AAK1) and disruption of this regulator may interrupt the passage of the virus into cells and the intracellular assembly of virus particles. Baricitinib has shown particularly high affinity for AAK1 and also binds cyclin G-associated kinase (GAK) another regulator of endocytosis. Further, there is growing interest in using baricitinib in combination with direct-acting antivirals, including lopinavir, ritonavir and remdesivir, since it has minimal interaction with the relevant cytochrome P450 drug-metabolising enzyme. However, there are also concerns with its use as baricitinib can inhibit a variety of inflammatory cytokines including interferon-α, which plays an important role in curbing virus activity.
While other JAK inhibitors such as ruxolitinib and fedratinib may also have activity against COVID-19, the predicted unbound plasma exposure required to inhibit receptor mediated endocytosis with these treatments greatly exceeds their tolerated doses. Therefore, they are unlikely to be suitable for patient with COVID-19 to reduce viral infectivity.
Recently, online news articles have listed JAK inhibitors, such as baricitinib, as potential COVID-19 treatment options.
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