Repurposing of Kinase Inhibitors for Treatment of COVID-19

Abstract

The outbreak of COVID-19, the pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an intense search for treatments by the scientific community. In the absence of a vaccine, the goal is to target the viral life cycle and alleviate the lung-damaging symptoms of infection, which can be lifethreatening. There are numerous protein kinases associated with these processes that can be inhibited by FDA-approved drugs, the repurposing of which presents an alluring option as they have been thoroughly vetted for safety and are more readily available for treatment of patients and testing in clinical trials. Here, we characterize more than 30 approved kinase inhibitors in terms of their antiviral potential, due to their measured potency against key kinases required for viral entry, metabolism, or reproduction. We also highlight inhibitors with potential to reverse pulmonary insufficiency because of their anti-inflammatory activity, cytokine suppression, or antifibrotic activity. Certain agents are projected to be dualpurpose drugs in terms of antiviral activity and alleviation of disease symptoms, however drug combination is also an option for inhibitors with optimal pharmacokinetic properties that allow safe and efficacious co-administration with other drugs, such as antiviral agents, IL-6 blocking agents, or other kinase inhibitors.

FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology

“…Interestingly, FYN inhibitors repurposed as a COVID-19 treatments 13 , have been also investigated as disease modifying treatments in AD 14 , supporting the convergence of common pathways between SARS-CoV-2 and AD in IFITM3's regulatory network.…”

Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

“…To take care of COVID-19 situation, various anti-inflammatory class of drugs are under trial and among them kinase inhibitors have emerged as one of the potential therapeutic modality to manage and treat COVID-19 infection [48]. These kinase inhibitors have shown 'one-drug-multiple target' properties and act on multiple proteins of the COVID-19 virus and hence, inhibit the viral entry, replication as well as mitigate the cascade of the cytokine storm [48]. As most of the cytokine inhibitors are approved for other indications, hence possess established safety and pharmacokinetic profile and therefore appears to be potential drug candidate for repurposing.…”

“…As most of the cytokine inhibitors are approved for other indications, hence possess established safety and pharmacokinetic profile and therefore appears to be potential drug candidate for repurposing. Thus, looking into these facts, kinase inhibitors, if found potent in mitigating COVID-19 induced complications would significantly minimize the time as well as the cost of drug development and can be accessible to the patients in a short span of time, as compared to an entirely new class of drugs [48]. Recently, Bouhaddou et al, 2020 published an extensive study showing the significant involvement of kinases in the pathogenesis of COVID-19 and thus, opened an avenue to target these kinases against COVID-19 infection [49].…”

“…Thus, JAK inhibitors, mainly JAK1 and JAK2 have been explored for the potential antiviral and anti-inflammatory effect in COVID-19 infection [52]. Among some of the established JAK inhibitors such as Baricitinib, Lestaurtinib, Ruxolitinib, Midostaurin, Lestaurtinib, Ruxolitinib, Fedratinib, and Tofacitinib, Baricitinib (an approved drug for rheumatoid arthritis) has shown potent protection against COVID-19 infection [48,[53][54][55]. Interestingly, Baricitinib when used at the same dose which was approved for rheumatoid arthritis, showed inhibition of AAK1 (P2-associated protein kinase-1) and GAK (cyclin G-associated kinase) which resulted into inhibition of viral entry via ACE-2 receptors and showed potent anti-inflammatory effect leading to reduction in cytokine storm [55].…”

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

“…While we concur, we would like to supplement this argument further with discussion of the effects on the differentiation and acquisition of effector function and the inclusion of nonapoptotic CD95 upstream signaling. Akt inhibition has also been proposed on the basis of an anti-viral effect (42)(43)(44). However, it appears that in presenting stages of Covid-19 disease antiviral agents seem to have questionable therapeutic benefit, possibly due to the disease entering an immunopathological stage of exuberant lymphocytic response (19).…”