Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release

Abstract

The Omicron variant has become dominant in the U.S. and around the world. This variant is found to be 2-fold more infectious than the Delta variant, posing a significant threat of severe cases and death. We and others have recently reported that the N-terminus domain (NTD) of the SARS-CoV-2 of various variants is responsible for inducing cytokine release in human PBMCs. Here, we demonstrate that the NTD of the Omicron variant remains highly effective at inducing cytokine release in human PBMCs. Furthermore, we show that Ponatinib and a novel compound, Olverembatinib, are potent Omicron NTD-mediated cytokine release inhibitors. Target profiling revealed that Olverembatinib blocks most of the previously identified kinases responsible for cytokine release. Together, we propose that Ponatinib and Olverembatinib may represent an attractive therapeutic option for treating moderate to severe COVID-19 cases. HIGHLIGHTSO_LIThe N-terminus domain (NTD) of the SARS-CoV-2 Omicron variant strongly induces multiple inflammatory molecules in PBMCs, unaffected by the mutations observed in the NTD. C_LIO_LIThe cytokine release mediated by the Omicron variant is comparable to the Delta variant. C_LIO_LIOlverembatinib, a clinical-stage multi-kinase inhibitor, potently inhibits Omicron NTD-mediated cytokine release. C_LIO_LIOlverembatinib could relieve severe symptoms associated with COVID-19 Omicron and Delta variants. C_LI