Researchers at the Human Biology Division, Fred Hutchinson Cancer Research Center in Washington, United States, have found that multi-kinase inhibitor Ponatinib is a potent inhibitor of the N-terminal domain (NTD)- mediated cytokine storm. The study is currently published on a pre-print server. Ponatinib is an FDA-approved drug and is used orally for the treatment of chronic myeloid leukemia.
The researchers aimed to identify drugs available for clinical use, which can help reduce the time needed to develop and distribute treatments to solve the COVID-19 pandemic. To arrive at the study findings, the team used spontaneously immortalized monocyte-like line, THP1(3) and mammalian (HEK293) cells that generated full-length Spike subunit S1 protein, which the SARS-CoV-2 needs to enter host cells. The team showed that 24-hour stimulation with the full-length mammalian cell-derived S1 subunit of SARS-CoV-2 spike protein led to massive upregulation of IL-1b in a dose-dependent manner.
Researchers found that the spike protein’s NTD from variants like B.1.1.7 and B.1.351 significantly induces various inflammatory molecules in monocytes and peripheral blood mononuclear cells. They identified many protein kinases, such as JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as vital downstream mediators of NTD-induced cytokine release. The study also identified Ponatinib as being able to inhibit the NTD-mediated cytokine storm effectively. Overall, the team proposed that agents targeting multiple kinases may be used as a therapeutic option to treat moderate to severe COVID-19.
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