Tyrosine Kinase Inhibitor Family of Drugs as Prospective Targeted Therapy for COVID-19 Based on In Silico And 3D-Human Vascular Lung Model Studies

Abstract

COVID-19 pandemic has ravaged the world and vaccines have been rapidly developed as preventive measures. But there is no target-based therapy which can be used if infection sets in. Remdesiver and dexamethasone were not designed to combat COVID-19 but are used clinically till better targeted therapies are available. Given this situation target based therapies that intervene in the disease pathway are urgently needed. Since COVID-19 genesis is driven by uncontrolled inflammation/thrombosis and protein kinases are critical in mounting this response, we explored if available tyrosine kinase inhibitors (TKIs) can be used as intervention. We profiled four TKIs namely; Lapatinib, Dasatinib, Pazopanib and Sitravatinib which inhibit tyrosine kinases but are completely distinct in their chemical structures. We demonstrate using in silico and an in vitro 3D-human vascular lung model which profiles anti-inflammatory and anti-thrombogenic properties that all four TKIs are active in varying degrees. Our findings that chemically different TKIs which share kinase inhibition as the common mechanism of action are active, strongly indicates that its a tyrosine kinase target-based activity and not off-target arbitrary effect. We propose that TKIs, approved for human use and widely available, can be rapidly deployed as specific target-based therapy for COVID-19.