PMC:7102591 / 26561-28716 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7102591","sourcedb":"PMC","sourceid":"7102591","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7102591","text":"As previously described in detail, SARS-CoV-2 enters targeted cells through receptor-mediated endocytosis [12]. Some of the identified regulators of clathrin-mediated endocytosis are members of the numb-associated kinase (NAK) family, such as AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) [101]. Inhibition of AAK1 may stop the access of the virus into lung cells and also the intracellular assembly of virus particles [102]. Of 47 AAK1 blockers approved for medical use, 6 inhibit AAK1 with high affinity. These include oncologic agents such as erlotinib, sunitinib, ruxolitinib, and fedratinib, which have all been demonstrated to inhibit infection of cells by Dengue virus, Ebola virus, and respiratory syncytial virus [103]. Unfortunately, all these compounds are able to produce adequate NAK inhibition only at doses significantly higher than those normally used in clinical practice and therefore potentially toxic for the patient [104,105]. Conversely, the JAK inhibitor baricitinib is able to effectively inhibit AAK1 and GAK at the plasma concentration obtained with the approved dosage for the treatment of RA (2 to 4 mg daily) [106]. Moreover, as a selective inhibitor of JAK 1 and 2, baricitinib is also able to produce an important dampening of host inflammatory response due to CRS (including IL-6 and interferon gamma) responsible for the more severe forms of interstitial pneumonia during COVID-19 [107,108]. Finally, the minimal interaction of baricitinib with the relevant CYP drug-metabolising enzymes makes the drug a possible candidate for inclusion in combination protocols with antiviral drugs such as lopinavir/ritonavir and remdesivir [109]. Interestingly, tofacitinib shows no detectable inhibition of AAK1 [104], whereas currently no data are available on the possible effect of other JAK inhibitors approved or tested for RA (such as upadacitinib or filgotinib) in relation to coronavirus infection. Unexpectedly, the only clinical trial evaluating the potential role of clathrin-mediated endocytosis blockade in the management of COVID-19 is currently ongoing with ruxolitinib 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