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 José C, Cunha Thiago M, Ekins Sean
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.
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.
ACS Omega. 2022 Aug 29;7(36):31935-31944. doi: 10.1021/acsomega.2c02794. eCollection 2022 Sep 13.
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 0.79 μM) while also showing a reduction of >3 log TCID/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.
目前，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）小分子药物的种类有限，只有少数几种已获批准（瑞德西韦）、紧急批准（地塞米松、巴瑞替尼、帕罗韦德和莫努匹拉韦）或正处于晚期临床试验阶段。凡德他尼是一种激酶抑制剂，可靶向血管内皮生长因子受体（VEGFR）、表皮生长因子受体（EGFR）以及RET酪氨酸激酶。在本研究中，它在不同细胞系中进行了测试，结果显示其对A549-hACE2细胞的抑制作用与毒性作用相比很有前景（半数抑制浓度为0.79 μM），同时对人冠状病毒229E（HCoV-229E）的半数组织培养感染剂量降低了>3 log TCID/mL。在SARS-CoV-2感染小鼠模型中评估了凡德他尼的体内疗效，结果显示其能显著降低白细胞介素-6（IL-6）、白细胞介素-10（IL-10）和肿瘤坏死因子-α（TNF-α）的水平，并减轻感染动物肺部的炎性细胞浸润，但并未降低病毒载量。与感染动物相比，凡德他尼还降低了趋化因子CCL2、CCL3和CCL4的水平。此外，凡德他尼还将SARS-CoV-2感染小鼠体内降低的干扰素-1β（IFN-1β）恢复到与未感染动物相似的水平。我们的结果表明，美国食品药品监督管理局（FDA）批准的抗癌药物凡德他尼作为一种潜在的治疗药物来阻断2019冠状病毒病（COVID-19）细胞因子风暴值得进一步评估。
