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

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Puhl, Ana C. ; Gomes, Giovanni F. ; Damasceno, Samara ; Fritch, Ethan J. ; Levi, James A. ; Johnson, Nicole J. ; Scholle, Frank ; Premkumar, Lakshmanane ; Hurst, Brett L. ; Lee-Montiel, Felipe ; Veras, Flavio P. ; Batah, Sabrina S. ; Fabro, Alexandre T. ; Moorman, Nathaniel J. ; Yount, Boyd L. ; Dickmander, Rebekah J. ; Baric, Ralph S. ; Pearce, Kenneth H. ; Cunha, Fernando Q. ; Alves-Filho, Jose C. ; Cunha, Thiago M. ; Ekins, Sean

• Document type: Journal article
• Source: ACS OMEGA; v. 7, n. 36, p. 10-pg., 2022-09-13.

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 (IC50 0.79 mu M) while also showing a reduction of >3 log TCID so /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-alpha 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-1 beta 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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/04860-8 - Global genome screening with CRISPRko libraries to identify essential factors in SARS-CoV2 infection and replication
• Grantee: Thiago Mattar Cunha
• Support Opportunities: Regular Research Grants