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

doi:10.1021/acsomega.2c02794

. 2022 Aug 29;7(36):31935-31944.

doi: 10.1021/acsomega.2c02794. eCollection 2022 Sep 13.

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

Ana C Puhl¹, Giovanni F Gomes², Samara Damasceno², Ethan J Fritch³, James A Levi⁴, Nicole J Johnson⁴, Frank Scholle⁴, Lakshmanane Premkumar³, Brett L Hurst^{5

6}, Felipe Lee-Montiel⁷, Flavio P Veras², Sabrina S Batah⁸, Alexandre T Fabro⁸, Nathaniel J Moorman^{3

9

10}, Boyd L Yount¹¹, Rebekah J Dickmander^{3

9

10}, Ralph S Baric^{3

9

11}, Kenneth H Pearce^{10

12}, Fernando Q Cunha², José C Alves-Filho², Thiago M Cunha², Sean Ekins¹

Affiliations

¹ Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.
² Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, Ribeirao Preto 14049-900, Sao Paulo, Brazil.
³ Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.
⁴ Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695-7001, United States.
⁵ Institute for Antiviral Research, Utah State University, Logan, Utah 84322-1400, United States.
⁶ Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322-1400, United States.
⁷ PhenoVista Biosciences, 6195 Cornerstone Ct E. #114, San Diego, California 92121, United States.
⁸ Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14090900, Brazil.
⁹ Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States.
¹⁰ Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
¹¹ Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States.
¹² UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, United States.

PMID: 36097511
PMCID: PMC9454268
DOI: 10.1021/acsomega.2c02794

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

Ana C Puhl et al. ACS Omega. 2022.

. 2022 Aug 29;7(36):31935-31944.

doi: 10.1021/acsomega.2c02794. eCollection 2022 Sep 13.

Authors

Affiliations

¹ Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.
² Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, Ribeirao Preto 14049-900, Sao Paulo, Brazil.
³ Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.
⁴ Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695-7001, United States.
⁵ Institute for Antiviral Research, Utah State University, Logan, Utah 84322-1400, United States.
⁶ Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322-1400, United States.
⁷ PhenoVista Biosciences, 6195 Cornerstone Ct E. #114, San Diego, California 92121, United States.
⁸ Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14090900, Brazil.
⁹ Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States.
¹⁰ Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
¹¹ Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States.
¹² UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, United States.

PMID: 36097511
PMCID: PMC9454268
DOI: 10.1021/acsomega.2c02794

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 μM) while also showing a reduction of >3 log TCID₅₀/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.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): S.E. and A.C.P. are employees of Collaborations Pharmaceuticals Inc.

Figures

**Figure 1**
Characterization of vandetanib. SARS-CoV-2 inhibition and cytotoxicity were tested in the A549-ACE2 cell line: (A) remdesivir (SI > 90) and (B) vandetanib (SI > 12.6). (C) HCoV229E antiviral assay with vandetanib.

**Figure 2**
Pseudo-SARS-CoV-2 D614G baculovirus (Montana Molecular #C1110G, #C1120G) assay in the presence of (A) vandetanib at 1 μM and its (B) graphical analysis.

**Figure 3**
In vivo efficacy of vandetanib in a mouse model of COVID-19. (A) Experimental timeline: K18-hACE2 tg mice mock or infected with SARS-CoV-2 (2 × 10⁴ PFU/40 μL saline, intranasal). Vandetanib group was treated with 25 mg/kg i.p. 1 h before virus infection. (B) Body weight was measured once a day. (C) Mice were euthanized after 3 dpi and (C) lung viral load and (D,E) lung histopathology was evaluated; ***p < 0.001 in comparison with the uninfected mock group after one-way ANOVA followed by a Tukey posthoc test; ###p < 0.001 in comparison with the infected group after one-way ANOVA followed by a Tukey posthoc test. Scale bar = 20×, 125 μm; 40×, 50 μm.

**Figure 4**
Vandetanib decreases lung inflammation in a mouse model of COVID-19. (A) Expression of IFN-1β quantified by qPCR. Levels of (B) IFN-1β, (C) IL-6, (D) TNF-α, (E) CCL4, (F) CCL2, (G) CCL3, (H) IL-10, (I) CXCL1, (J) CXCL2, and (K) CXCL10 measured by ELISA; *p < 0.05, **p < 0.01, and ***p < 0.001 in comparison with mock group after one-way ANOVA followed by a Tukey posthoc test; #p < 0.05 and ##p < 0.01 in comparison with the infected group after one-way ANOVA followed by a Tukey posthoc test.

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References

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[1] Rehman M. F. U.; Fariha C.; Anwar A.; Shahzad N.; Ahmad M.; Mukhtar S.; Farhan Ul Haque M. Novel coronavirus disease (COVID-19) pandemic: A recent mini review. Comput. Struct Biotechnol J. 2021, 19, 612–623. 10.1016/j.csbj.2020.12.033. - DOI - PMC - PubMed

[2] Rehman M. F. U.; Fariha C.; Anwar A.; Shahzad N.; Ahmad M.; Mukhtar S.; Farhan Ul Haque M. Novel coronavirus disease (COVID-19) pandemic: A recent mini review. Comput. Struct Biotechnol J. 2021, 19, 612–623. 10.1016/j.csbj.2020.12.033. - DOI - PMC - PubMed

[3] Kyriakidis N. C.; López-Cortés A.; González E. V.; Grimaldos A. B.; Prado E. O. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. NPJ. Vaccines 2021, 6 (1), 28.10.1038/s41541-021-00292-w. - DOI - PMC - PubMed

[4] Kyriakidis N. C.; López-Cortés A.; González E. V.; Grimaldos A. B.; Prado E. O. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. NPJ. Vaccines 2021, 6 (1), 28.10.1038/s41541-021-00292-w. - DOI - PMC - PubMed

[5] Huang H. Y.; Wang S. H.; Tang Y.; Sheng W.; Zuo C. J.; Wu D. W.; Fang H.; Du Q.; Li N. Landscape and progress of global COVID-19 vaccine development. Hum. Vaccin. Immunother. 2021, 17, 3276–3280. 10.1080/21645515.2021.1945901. - DOI - PMC - PubMed

[6] Huang H. Y.; Wang S. H.; Tang Y.; Sheng W.; Zuo C. J.; Wu D. W.; Fang H.; Du Q.; Li N. Landscape and progress of global COVID-19 vaccine development. Hum. Vaccin. Immunother. 2021, 17, 3276–3280. 10.1080/21645515.2021.1945901. - DOI - PMC - PubMed

[7] Eastman R. T.; Roth J. S.; Brimacombe K. R.; Simeonov A.; Shen M.; Patnaik S.; Hall M. D. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020, 6 (5), 672–683. 10.1021/acscentsci.0c00489. - DOI - PMC - PubMed

[8] Eastman R. T.; Roth J. S.; Brimacombe K. R.; Simeonov A.; Shen M.; Patnaik S.; Hall M. D. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020, 6 (5), 672–683. 10.1021/acscentsci.0c00489. - DOI - PMC - PubMed

[9] Kalil A. C.; Patterson T. F.; Mehta A. K.; Tomashek K. M.; Wolfe C. R.; Ghazaryan V.; Marconi V. C.; Ruiz-Palacios G. M.; Hsieh L.; Kline S.; Tapson V.; Iovine N. M.; Jain M. K.; Sweeney D. A.; El Sahly H. M.; Branche A. R.; Regalado Pineda J.; Lye D. C.; Sandkovsky U.; Luetkemeyer A. F.; Cohen S. H.; Finberg R. W.; Jackson P. E.H.; Taiwo B.; Paules C. I.; Arguinchona H.; Erdmann N.; Ahuja N.; Frank M.; Oh M.-d.; Kim E.-S.; Tan S. Y.; Mularski R. A.; Nielsen H.; Ponce P. O.; Taylor B. S.; Larson L.; Rouphael N. G.; Saklawi Y.; Cantos V. D.; Ko E. R.; Engemann J. J.; Amin A. N.; Watanabe M.; Billings J.; Elie M.-C.; Davey R. T.; Burgess T. H.; Ferreira J.; Green M.; Makowski M.; Cardoso A.; de Bono S.; Bonnett T.; Proschan M.; Deye G. A.; Dempsey W.; Nayak S. U.; Dodd L. E.; Beigel J. H. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J. Med. 2021, 384 (9), 795–807. 10.1056/NEJMoa2031994. - DOI - PMC - PubMed

[10] Kalil A. C.; Patterson T. F.; Mehta A. K.; Tomashek K. M.; Wolfe C. R.; Ghazaryan V.; Marconi V. C.; Ruiz-Palacios G. M.; Hsieh L.; Kline S.; Tapson V.; Iovine N. M.; Jain M. K.; Sweeney D. A.; El Sahly H. M.; Branche A. R.; Regalado Pineda J.; Lye D. C.; Sandkovsky U.; Luetkemeyer A. F.; Cohen S. H.; Finberg R. W.; Jackson P. E.H.; Taiwo B.; Paules C. I.; Arguinchona H.; Erdmann N.; Ahuja N.; Frank M.; Oh M.-d.; Kim E.-S.; Tan S. Y.; Mularski R. A.; Nielsen H.; Ponce P. O.; Taylor B. S.; Larson L.; Rouphael N. G.; Saklawi Y.; Cantos V. D.; Ko E. R.; Engemann J. J.; Amin A. N.; Watanabe M.; Billings J.; Elie M.-C.; Davey R. T.; Burgess T. H.; Ferreira J.; Green M.; Makowski M.; Cardoso A.; de Bono S.; Bonnett T.; Proschan M.; Deye G. A.; Dempsey W.; Nayak S. U.; Dodd L. E.; Beigel J. H. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J. Med. 2021, 384 (9), 795–807. 10.1056/NEJMoa2031994. - DOI - PMC - PubMed

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

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

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Conflict of interest statement

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Abstract

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