Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

Abstract

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC 50 0.79 μM) while also showing a reduction of >3 log TCID 50 /mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1β caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.

Discovery of PLpro and Mpro Inhibitors for SARS-CoV-2

“…We previously identified vandetanib, a vascular endothelial growth factor (VGFR) inhibitor, with activity against SARS-CoV-2 in A549 − ACE2 cells, which blocked the cytokine storm in infected mice. 19 We then evaluated other kinase inhibitors against PL pro and M pro and showed that olmutinib inhibits PL pro with an IC 50 = 0.54 ± 0.04 μM (Figure 3A), dacomitinib with an IC 50 = 3.33 ± 0.06 μM (Figure 3B), crizotinib with an IC 50 = 3.81 ± 0.04 μM (Figure 3C), and bosutinib with an IC 50 = 4.23 ± 0.28 μM (Figure 3D) were similarly active. None of the kinase inhibitors demonstrated inhibition with M pro .…”

“…69 FDA-approved small-molecule kinase inhibitors could potentially be repurposed as antivirals because many kinase host targets are necessary or required for the viral life cycle, replication, and infection of multiple virus types. 70 We recently demonstrated that vandetanib blocks the cytokine storm in mice infected by SARS-CoV-2, 19 which prompted us to evaluate other kinase inhibitors against PL pro and M pro . Here, we have demonstrated for the first time that olmutinib, bosutinib, dacomitinib, and crizotinib are PL pro inhibitors, and this may contribute alongside any host effects the compounds may have.…”

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

“…Also, studies showed that 31 inhibits in vitro cytokine release in myeloid cells and in vivo in lung inflammation mouse models [ 276 ]. Biological investigations disclosed that vandetanib ( 32 ) inhibits SARS-CoV-2 in A549 cells expressing ACE2 (A549-hACE2) with an IC 50 value of 0.79 μM as well as it suppresses HCoV-229E proliferation [ 277 ]. In addition, studies proposed that 32 impede COVID-19 cytokine storm in mice models [ 277 ].…”

“…Biological investigations disclosed that vandetanib ( 32 ) inhibits SARS-CoV-2 in A549 cells expressing ACE2 (A549-hACE2) with an IC 50 value of 0.79 μM as well as it suppresses HCoV-229E proliferation [ 277 ]. In addition, studies proposed that 32 impede COVID-19 cytokine storm in mice models [ 277 ]. The in vivo findings revealed that 32 decreases IL-6 and 10, TNF-α, and inflammatory infiltrate in infected mice lungs without decreasing viral titers [ 277 ].…”

“…In addition, studies proposed that 32 impede COVID-19 cytokine storm in mice models [ 277 ]. The in vivo findings revealed that 32 decreases IL-6 and 10, TNF-α, and inflammatory infiltrate in infected mice lungs without decreasing viral titers [ 277 ].…”